First line anti MTB includes, rifampicin, INH, pyrazinamide, ethambutol
The average concerns regarding medications, including anti-MBT pharmaceuticals, are efficacy, safety, drug-drug interactions, adverse effects, toxicity, and cost.
Utilization of anti-TB drugs after SOT Concern exists regarding drug interactions with other immunosuppressive medications, specifically CNI (Tacrolimus, cyclosporine), mTOR inhibitors such as sirolimus and everolimus, antimetabolites (azathioprine and MMF), and steroids.
RIFAMPICIN
Rifampicin is considered the first-line anti-tuberculosis drug due to its high bactericidal activity against mycobacteria. It inhibits protein synthesis by inhibiting mRNA transcription and synthesis, and it is metabolized by the liver. Rifampicin acts as an enzyme inducer via cytochrome 450, CYP3A4, and induces certain drug transporter proteins, including intestinal and hepatic P-glycoprotein. and can reduce the level of CNI, sirolimus, and everolimus to undetectable levels, so we need to increase the dose of tacrolimus or Cyclosporine by 3-5 folds (sometimes will give TID dose) with close monitoring by trough level, also need frequent LFT monitoring for transaminitis weekly in the first two months then every month, rifabutin as an alternative can be used, and it’s more well-tolerated than rifam Dose: rifampicin 600 mg/d; rifabutin 300 mg/d.
Sirolimus follows the same protocol as CNI and requires frequent dose adjustments and monitoring.
No interaction between azathioprine, MMF, and rifampin resulted in a decrease in MMF concentration due to enterohepatic circulation.
INH
Isoniazid and rifamycin can cause drug-induced hepatitis, and rifampicin and pyrazinamide can cause severe liver toxicity (3). Therefore, close monitoring is required twice per week for the first two weeks, then once per week for the first two months; if liver enzymes increase fivefold from baseline, discontinuation should be considered.
INH and hormones
Prednisolone significantly decreased the plasma concentrations of isoniazid in both slow and rapid inactivators (2).due to increased renal clearance of isoniazid in both slow and rapid inactivators and an increased rate of acetylation of isoniazid in slow inactivators, but concomitant administration of rifampin significantly modified the effect of prednisolone on isoniazid disposition.
MMF combined with azathioprine, sirolimus, and CNI
Reference: Sorohan, B. M., Ismail, G., Tacu, D., Obrișcă, B., Ciolan, G., Gîngu, C., Sinescu, I., & Baston, C. (2022). Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. In Pathogens (Vol. 11, Issue 9). https://doi.org/10.3390/pathogens11091041
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
Rifampicin: first-line anti-TB drug
· Rifampicin is an enzyme inducer of CYP34A(Rifabutin is a less potent cytochrome inducer), thus increasing the metabolism of CNIs (Tacrolimus, cyclosporine) and MTORs (Sirolimus and Everolimus). Moreover, it reduces the levels of prednisone (increases clearance by around 45% and reduce the amount of drug available to the tissues by around 66%) and MMF due to interaction with entero-hepatic circulation.. However, it has no effect on Azathioprine.
· Accordingly, we need to increase the dose of CNIs(3-5 times), Sirolimus if used and possibly steroids and MMF. Close monitoring of immunosuppression and checking trough levels of CNIs is required with the initiation and after the discontinuation of rifampicin or rifabutin.
Isoniazid: first-line anti-TB drug
· INH increases the metabolism and renal clearance of prednisolone. So, decreases INH effectiveness. INH has no effects on anti-metabolites(MMF and azathioprine) CNIs and sirolimus.
We have to be aware that both Rifampicin and INH are hepato-toxic. Thus close monitoring of liver functions is required twice weekly in the first two weeks then weekly in the first two months and discontinue treatment if liver enzymes increases by 5 folds from baseline.
References:
1. Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother. 1980 Nov;18(5):661-6.
2. Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76.
● Rifampicin decrease the levels of CNi , mTORi and affects steroid metabolization,
and even mycophenolate mofetil (MMF) by inducing CYP3A4-mediated immunosuppressant metabolism
which increases the risk of rejection
☆ Therefore calcineurin and mTOR inhibitors levels should be monitored and increased three- and five-fold and the glucocorticoid dose should be doubled
☆ An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 or fluoroquinolones
● Concomitant administration of INH and CyA is safe and is not associated with any appreciable alterations in the bioavailability of CyA neither MMF, TAC, AZA, m-TOR .
References :
1) . Phyo Wai Lwin,Yi Yi Htun, Aung Kyaw Myint, and Htar Kyi Swe . Posttransplantation tuberculosis management in terms of immunosuppressant cost: a case report in Myanmar .Korean J Transplant. 2021 Mar 31; 35(1): 48–52.
2) . K Sud et al.Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients .Methods Clin Pharmacol. 2000 Oct.
Rifampicin decreases the level of Tacrolimus,cyclosporine and sirolimus.It also decreases the bioavailablity of Mycophenolate and prednisolone. No interaction between azathioprine and rifampicin.
INH effects on immunosuppression-
No interaction found except with Cyclosporine where it may decrease the level the cyclosporine but many reported no effect on bioavailablity.
Anti TB drugs and
1-Rifambin :
May cause decrease in taclolimus,cyclosporine and sirolimos level ,
Increase in mycophinolate level,no interaction with azathioprine.
2_INH:
Cause no interaction with tacrolimus, cyclosporine,MMF , Azathioprine.
Predlone may decrease INH level.
Anti-TB drugs are: rifampicin, INH, pyrazinamide, ethambutol. There are concerns about their effects on the metabolism of immunosuppressive drugs such as tacrolimus, sirolimus, MMF or AZA and prednisolone.
Rifampicin is an anti-TB with potent and bactericidal effect by blocking mRNA synthesis which is metabolized by liver.
It induces cytochrome P450, CYP3A4, and some drug transporters like p-glycoproteins.
So it reduces blood levels of tacrolimus and cyclosporine, sirolimus.
The dose of these drugs especially CNIs should be increase to 3 to 5 folds to have the same drug levels and close drug level and LFT monitoring are needed.
Sirolimus needs higher doses and close monitoring too. Rifampicin reduces MMF level by interaction with enterohepatic circulation but has no effect on azathioprine level.
INH is hepatotoxic especially in combination with rifampicin and LFT monitoring twice weekly and then weekly is preformed and in case of 5-fold increase, discontinuing is considered. Prednisolone causes significant decrease in isoniazid concentration by increasing the rate of acylation of INH.
MMF and azathioprine and CNI have no effect on INH level.
Reference:
Sorohan, B. M., Ismail, G., Tacu, D., Obrișcă, B., Ciolan, G., Gîngu, C., Sinescu, I., & Baston, C. (2022). Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. In Pathogens (Vol. 11, Issue 9). https://doi.org/10.3390/pathogens11091041
The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein.
TACROLIMUS:
– Rifampicin: decrease tacrolimus exposure – INH: no effect
CYCLOSPORINE:
– Rifampicin: Decreased cyclosporine exposure – INH: no effect
SIROLIMUS:
– Rifampicin: Decreased sirolimus exposure – INH: no effect
AZATHIOPRINE:
– Rifampicin: – INH:
MYCOPHENOLATE MOFETIL
– Rifampicin: Decreased MPA exposure – INH: no coments
– Wang YC, Salvador NG, Lin CC, Wu CC, Lin TL, Lee WF, Chan YC, Chen CL, Co JS, Encarnacion DD. Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. Biomed J. 2021 Dec;44(6 Suppl 2):S162-S170. doi: 10.1016/j.bj.2020.08.010. Epub 2020 Sep 4. PMID: 35300949; PMCID: PMC9068555.
Rifampicin, a potent inducer of cytochrome p450 3A4 and p-glycoprotein, interferes with immunosuppression metabolism and decrease the level of CNI (cyclosporin, tacrolimus), Therefore it is suggested to closely monitoring of CNI or mTORi levels while using Rifampicin. mTOR inhibitors (sirolimus, everolimus) are affecting glucocorticoid metabolism. therefore CNI and mTOR inhibitors dose should be increased between three and five-fold
Rifampicin increases MPA metabolism by induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases,
Rifampicin increases the metabolism of cortisol, increasing clearance by 45%, thereby lowering prednisolone AUC by 66% and reducing its half-life by 40-60%. higher steroid doses may be required during co-administration with rifampicin in order to counter these effects
INH have no significant drug interaction with the given medication
Rifampicin, a potent inducer of cytochrome p450 3A4 and p-glycoprotein, interferes with immunosuppression metabolism and decrease the level of CNI (cyclosporin, tacrolimus), mTOR inhibitors (sirolimus, everolimus) and affects glucocorticoid metabolism. So dose of CNI and mTOR inhibitors should be increased between three and five-fold and the glucocorticoid dose should be doubled during treatment.
INH have no significant drug interaction with the given medication.
1. Calcineurin inhibitors (Tacrolimus, Cyclosporine) and mTORi Sirolimus · Rifampicin being a potent inducer of cytochrome P450 enzymes (CYP3A4 & CYP3A5) as well as P. glycoprotein in the liver – leads to increased metabolism of CNI (tacrolimus, cyclosporine) and mTORi (Sirolimus), thereby decreases the plasma levels of CNI and Sirolimus to subtherapeutic levels, thus increases risk of allograft rejection. – ATT induced hepatitis on the other hand, can have bizarre effect on drug metabolism, can increase the level of CNI causing nephrotoxicity. – KDIGO guidelines suggests close monitoring of CNI or mTORi levels while using Rifampicin.
Clinical effects of Isoniazid interaction with CNI, Sirolimus and the change in plasma level of these drugs is not very significant.
2. Azathioprine
Neither Rifampicin nor INH show any interaction with Azathioprine.
3. Mycophenolate Mofetil
Rifampicin increases MPA metabolism by induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases, however the interaction is much less pronounced than that between CNI and rifampicin.
– It could potentially lead to MPA underexposure and loss of clinical efficacy, may need dose adjustment of mycophenolate.
There is no clinically significant effect of INH on MMF. Co-administration of isoniazid with antimetabolites can synergistically intensify bone marrow suppression leading to anaemia, pancytopenia.
4. Prednisone · Rifampicin increases the metabolism of cortisol, increasing clearance by 45%, thereby lowering prednisolone AUC by 66% and reducing its half-life by 40-60%. higher steroid doses may be required during co-administration with rifampicin in order to counter these effects. · Isoniazid increases serum prednisone levels by inhibition of CYP3A4 induction. References: 1. Bhagat V, Pandit RA, Ambapurkar S, et al. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021; 25(1): 67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296. 2. British National Formulary [Internet]. NICE. [cited 2023Mar5]. Available from: https://bnf.nice.org.uk/  3. KDIGO clinical practice guideline for the care of kidney transplant recipients: A Summary [Internet]. [cited2023Mar5]. Available from: https://kdigo.org/wp-content/uploads/2017/02/KITxpGL_summary.pdf 4. Naylor H, Robichaud J. Decreased tacrolimus levels after administration of rifampin to a patient with renal transplant. Can J Hosp Pharm. 2013 Nov;66(6):388-92. Available from: https://pubmed.ncbi.nlm.nih.gov/24357873/ 5. Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clinical pharmacology and therapeutics. 2005 Jul;78(1):81-8. PubMed PMID: 16003296. Epub 2005/07/09.
6. Matre V ET, Satyanarayana G, Page RL, et al. Pharmacokinetic Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids. Ann Transplant. 2018 Jan 23; 23: 66-74. doi: 10.12659/aot.906164. PMID: 29358572; PMCID: PMC6248062.
1) Interaction between Rifampicin (CYP3A4 Inducer) and:
· Tacrolimus: Rifampicin may decrease the serum concentration of Tacrolimus.
· Cyclosporine: Rifampicin may decrease the serum concentration of Cyclosporine
· Sirolimus: Rifampicin may decrease the serum concentration of Sirolimus
· Azathioprine: no interaction with Rifampicin
· Mycophenolate Mofetil: Rifampicin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
· Prednisone: Rifampicin may decrease the serum concentration of Prednisone.
Reduces level of Tacrolimus- Cyclosporine- sirolimus- MMF- prednisolone
●inducer of CYP 450 3A4-mediated metabolism ●P glycoprotein-mediated efflux of sirolimus by rifampicin
●Interference of enterohepatic circulation of MMF by rifampicin
HOWEVER rifampicin doesn’t interfere with Azathioprine
INH
Using prednisone with INH deceased the level of INH because it increases renal clearance of the INH and inactivation
THere is no interference between INH and Tacrolimus- Cyclosporine- Sirolimus- azathioprine – MMF
Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein. Drugs which are metabolized by these enzymes have interaction with Rifampicin –CNIs (cyclosporine, tacrolimus), mTOR inhibitors levels are decreased with Rifampicin so their dose should be increased 3-5 fold before starting this drug in order to reduce the chances of rejection.
INH inhibit CP450 3A4 inhibitor and monoamine oxidases, therefore, drugs like CNIs , mTOR inhibitors levels will be increased and need dose reduction while using this drug.
Both drugs have effect on steroids and Mycophenolate mofetil. Steroids will decrease the level of INH ,however, Rifampicin will increase the metabolism of prednisolone and its clearance. Rifampicin induces Uridine diphosphate-glucuronosyltransferases which will increase glucuronidation of mycophenolic acid by the liver, thus reducing entero-hepatic recirculation and also absorption of mycophenolic acid leading to their reduce level. However, concomitant use of INH with MMF can cause hepatotoxicity and cytopenias.
In short, drug levels should be monitored frequently to avoid side effects and lessen the chances of rejection.
REFERENCE:
1-Sorohan, B.M.; Ismail, G.; Tacu, D.; et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041.
2-Aguado JM, Torre-Cisneros J, Fortun J. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish society of infectious diseases and clinical microbiology. Clin Infect Dis. 2009;48(9):1276–1284.
Rifampicin and Rifabutin are known to induce the enzymes of CYP3A4….Isoniazid does not induce the metabolism of CYP3A4 and hence no interaction with immunosuppressants are noted with isoniazid
Rifampcin is an enzyme inducer….Decrease the level of calcineurin inhibitors, mTOR inhibitors leading to acute graft rejection…. Tacrolimus , cyclosporine and sirolimus levels are reduced in the serum when patients are on rifampicin….Levels of prednisolone are also reduced while of rifampicin….there is no effect of rifampicin on azathioprine metabolism….. MMF is metabolized into Mycophenolic acid which undergoes glucuronidation by uridine diphosphate glucouronosyl transferase in the liver and kidney to an inactive metabolite…rifampicin induces the enzyme of UGT and decreases the level of MMF active metabolite….
Isoniazid is a CYP3A4 inhibitor but it is a weaker inhibitor as compared to Rifampicin…. Concomitant use of INH with MMF may exert more bone marrow cytopenia
Rifampicin is strong inducer of enzyme CYP3A4. It is associated with increased metabolism of CNIs and mTOR, therefore the levels of these drugs are reduced. The dose of CNI and mTOR needs to be increased 2-5 time with monitoring of trough levels and monitoring for rejection. The effect of Rifampicin on MMF is less pronounced compared with CNI and MTOR, but is associated with lower MMF levels. There is no interaction of Rifampicin with AZA. Rifampicin reduces the effects of steroids so dose should be increased up to 2 times. Isoniazid is a CYP3A4 enzyme inhibitor, leading to increased levels of CNI and mTOR, the effect on these drugs is not significant. Concomitant use of INH with MMF/AZA increases bone marrow suppression. Use of Steroids and Isoniazid together is associated with reduced levels of isoniazid .
Rifampicin is a potent cytochrome P3A4 inducer [CYP3A4]. As such it induces metabolism of calcineurin inhibitors, mammalian target of rapamycin inhibitors, mycophenolate mofetil and steroids. As a result of this action it significantly reduces the blood trough levels of Tacrolimus, cysclosporine. Sirolimis , mycophenolate mofetil and Prednisone.
Isoniazid is an inhibitor of the cytochrome P450 system, and the result of this effect is that it will increase the trough levels of the afor mentioned medications. A study by Sud K et al showed hpwever, that this did nmot happen with their patients
REFERENCES
Yu-Chen Wang et al.Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. biomedicL Journal. Volume 44. Issue 6. December 2021 Sud K, Muthukumar T, Singh B, Garg SK, Kohli HS, Jha V, Gupta KL, Sakhuja V. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients. Methods Find Exp Clin Pharmacol. 2000 Oct;22(8):647-9. doi: 10.1358/mf.2000.22.8.802278. PMID: 11256238
1) Interaction between Rifampicin (CYP3A4 Inducer) and:
· Tacrolimus: Rifampicin may decrease the serum concentration of Tacrolimus.
· Cyclosporine: Rifampicin may decrease the serum concentration of Cyclosporine
· Sirolimus: Rifampicin may decrease the serum concentration of Sirolimus
· Azathioprine: no interaction with Rifampicin
· Mycophenolate Mofetil: Rifampicin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
· Prednisone: Rifampicin may decrease the serum concentration of Prednisone.
2) Interaction between INH (CYP3A4 Inhibitor) and:
· Tacrolimus: INH may increase the serum concentration of Tacrolimus
· Cyclosporine: INHmay increase the serum concentration of Cyclosporine
· Sirolimus: INHmay increase the serum concentration of Sirolimus
· Azathioprine: no interaction with INH
· Mycophenolate Mofetil: no interaction with INH
· Prednisone: may decrease the serum concentration of Isoniazid.
Drug interactions of Anti Tubercular Rifampicin, INH with ImmunosuppressantTacrolimus, Cyclosporine, Sirolimus, Azathioprine, Mycophenolate Mofetil, Prednisone:
· Rifampicin is a potent enzyme inducer of cytochrome P 450, so reduce the levels of CNI (Tacrolimus, Cyclosporine), mTOR inhibitors (Sirolimus) and corticosteroids ( Prednisone ).Thus will lead to low levels of Cyclosporine, Tacrolimus, Sirolimus and Prednisolone. · Rifampicin does not affect metabolism of antimetabolites (MMF and Azathioprine) but concomitant use may worsen adverse events like cytopenias. · On the other hand Isoniazid is an inhibitor of cytochrome P450 thus it will increase the levels of CNI (Tacrolimus, Cyclosporine), mTOR inhibitors (Sirolimus) and corticosteroids (Prednisone) though this effect is not significant. · Isoniazid also cause cytopenias. So, it will worsen cytopenia caused by MMF and azathioprine if given concurrently. Reference: Medscape UpToDate
RFM is a strong cytochrome (CY) P3A4 inducer. RFM can significantly reduce blood levels of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi) through induction of P-glycoprotein mediated efflux transport mediating mTORi metabolism so the dose of CNIs and mTORs should be increased by 3-5 fold,
RFM reduces blood levels of mycophenolate mofetil (MMF) “that is better be reduced or held for 2 months in active TB ” through induction of uridine diphosphate glucuronosyltransferases, which mediate MMF metabolism
RFM affects the metabolization of glucocorticoid, and the dose of the steroid should be increased up to 2 fold
so for the interactions mentioned above, RFB is preferred being a less enzyme inducer
INH, though a weak enzyme inducer, no direct interactions with the immunosuppressants are strongly suggested but it may increase the risk of adverse events caused by other anti-tuberculous drugs
reference
M. Niemi, J.T. Backman, M.F. Fromm, P.J. Neuvonen, K.T. Kivisto Pharmacokinetic interactions with rifampicin clinical relevance Clin Pharmacokinet, 42 (2003), pp. 819-850
in general rifampicin is inducer of cytochrome P450 enzyme in liver which increases metabolism and REDUCES THE DRUG LEVEL IN BLOOD of tacrolimus, cyclosporin , sirolimus , and even steroids
this start within hours of taking rifampicin and peaks at 2 weeks and same time is required to return to baseline
CNI dose need to be increased 3 folds , steroid dose need 2 fold increases with intense serum level monitoring
Level of MMF is also reduced but not so intensely with the use of rifampicin
Refabutin is a better replacement of rifampicin with less effect of immunosuppression drugs
on the contrary isoniazide INH inhibits the cytochrome P450 enzyme and drug level can get ELEVATED leading to more immunosuppression and drug toxicity
INH is a WEAK inhibitor of cytochrome P450
Calcineurin inhibitors (Tacrolimus, Cyclosporine) and Sirolimus
Rifampicin decreases the plasma levels of CNI and mTOR inhibitors (Sirolimus) by inducing CYP3A4 enzymes as well as P-glycoprotein and thus may lead to acute graft rejection.
Isoniazid increases the levels of Sirolimus, Tacrolimus and Cyclosporine by inhibiting CYP450 3A4 enzymes and monoamine oxidases, but the effect of INH on these drugs is may not be very significant.
Azathioprine
Neither Rifampin nor INH show any interaction with Azathioprine.
Mycophenolate Mofetil
Rifampin increases MPA metabolism by induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases. Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy.
There is no clinically significant effect of INH on MMF. Co-administration of isoniazid with antimetabolites can produce deletrious effects on bone marrow ie. bone marrow suppression leading to anaemia, leukopenia and thrombocytopenia.
Prednisone
Rifampin increases the metabolism of cortisol, thereby lowering prednisolone AUC by 66% and increasing clearance by 45%. When patients were treated with prednisone and rifampin it was found that prednisolone clearance increased by greater than 200% and half-life decreased by 40% to 60% compared to prednisolone administration without rifampin.
Isoniazid increases serum prednisone levels by inhibition of CYP3A4 induction. Prednisone decreases plasma Isoniazid concentrations in both slow and rapid acetylators.
References:
Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clinical pharmacology and therapeutics. 2005 Jul;78(1):81-8. PubMed PMID: 16003296. Epub 2005/07/09. eng
Van Matre ET, Satyanarayana G, Page 2nd RL, Levi ME, Lindenfeld J, Mueller SW. Pharmacokinetic Drug-Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids. Ann Transplant. 2018 Jan 23;23:66-74. doi: 10.12659/aot.906164. PMID: 29358572; PMCID: PMC6248062.
Rifampicin is an inducer of P glycoprotein transporter and CYP3A4 while isoniazid is an inhibitor of CYP3A4.
As an inducer, Rifampicin lowers drug levels of ;Mycophenolate mofetil, prednisone, sirolimus, tacrolimus and cyclosporine via increased intestinal and liver metabolism and also an efflux of p glycoprotein(MDR1) transporter.
As an enzyme CYP3A4 inhibitor ,Isoniazid has been documented to elevate levels of sirolimus, Tacrolimus and prednisone and thus close monitoring or alternative medication sorted.
Isoniazid increases bone marrow suppressive effects of antimetabolites when given concurrently but no significant DI.
REF;
Bogdan et al ; MTB infection after kidney transplantation; A comprehensive review.
a) Rifampicin and tacrolimus/cyclosporine
Rifampicin is coded by the British National Formulary (BNF) as having a severe interaction with calcineurin inhibitors (CNI) such as tacrolimus and cyclosporine. Tacrolimus is a CYP3A4 inhibitor, whilst rifampicin is a inducer of this enzyme pathway. The danger of the interaction is that, as a potent inducer of the liver cytochrome P450 enzymes (CYP3A4 & CYP3A5), rifampicin leads to increased metabolism of tacrolimus/cyclosporine which may subsequently produce subtherapeutic immunosuppression levels putting the patient at risk of allograft rejection. If the two medications are co-prescribed, close monitoring of CNI levels must be undertaken and an increased CNI dose requirement should be anticipated.
b) Rifampicin and sirolimus
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is also coded by the BNF as having a severe interaction with rifampicin due to cytochrome P450 enzyme induction: increased metabolism of sirolimus potentially results in subtherapeutic immunosuppression levels increasing the risk of allograft rejection. KDIGO guidelines advise that the same TB prophylaxis or treatment regime can be used for kidney transplant recipients as for the local general population; however, close monitoring of CNI or mTORi levels is imperative and where possible clinicians should consider whether rifampicin could be substituted with rifabutin to reduce the risk of this significant interaction and also the risk of acute kidney injury associated with rifampicin.
c) Rifampicin and azathioprine
No significant interaction
d) Rifampicin and mycophenolate mofetil
Mycophenolate mofetil is also coded by the BNF as having a severe interaction with rifampicin- this is owing to the increased metabolism of mycophenolate which can expose the patient to insufficient immunosuppression and risk allograft rejection (particularly with long term use). However, the interaction is much less pronounced that that between CNI and rifampicin. The need for dose adjustment of mycophenolate should be anticipated.
e) Rifampicin and prednisolone
Rifampicin is coded by the BNF as having a moderate interaction with prednisolone. It is recognised that rifampicin can decrease the effectiveness of prednisolone (increased metabolism through rifampicin being an inducer of liver enzymes resulting in lower plasma levels of prednisolone). Clinicians should be aware that higher steroid doses may be required during co-administration with rifampicin in order to counter these effects.
2. Isoniazid
a) Isoniazid and tacrolimus/cyclosporine
Although co-prescription of Isoniazid and tacrolimus may have some small effect on trough CNI levels, the clinical impact of this is not reported to be significant and therefore the BNF does not list isoniazid as a drug which interacts with tacrolimus or cyclosporine.
b) Isoniazid and sirolimus
No clinically significant interaction is noted between isoniazid and sirolimus.
c) Isoniazid and azathioprine
Isoniazid does not have any clinically significant effect on the metabolism of azathioprine. However, prescribers should be mindful of the recognised side-effects of isoniazid which include hepatotoxicity and agranulocytosis. Bone marrow depression (dose related) is recognised in the BNF as a common side effect of azathioprine, alongside hepatotoxicity and agranulocytosis which occur less frequently. Careful monitoring is advisable during co-prescription of these medications to avoid bone marrow over-suppression and dose adjustment may be required in view of this.
Does Isoniazid have an additive effect on the bone marrow?
The mechanism through which azathioprine and isoniazid cause myelosuppression is not clearly defined. However, the myelotoxic effects of both medications on an individual basis are among the more common medication causes of bone marrow toxicity and therefore the risk/benefit of co-prescribing both medications simultaneously must be very carefully considered and, if indicated, the lowest possible dose should be used in conjunction with careful blood count monitoring.
d) Isoniazid and mycophenolate mofetil
Mycophenolate is not listed in the BNF as having a clinically significant interaction with isoniazid. However, prescribers must be mindful of both isoniazid and mycophenolate’s recognised side-effects on the bone marrow and careful full blood count monitoring is important.
e) Isoniazid and prednisolone
Although it is recognised that prednisolone can reduce the plasma concentration of isoniazid this interaction is not usually clinically significant and as such there is not a significant interaction when considering co-prescription of the two medications.
References:
British National Formulary [Internet]. NICE. [cited 2023Mar5]. Available from: https://bnf.nice.org.uk/
Naylor H, Robichaud J. Decreased tacrolimus levels after administration of rifampin to a patient with renal transplant. Can J Hosp Pharm. 2013 Nov;66(6):388-92. Available from: https://pubmed.ncbi.nlm.nih.gov/24357873/
Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Chapter 16 – Hematopoietic System, Editor(s): Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Fundamentals of Toxicologic Pathology (Second Edition), Academic Press, 2010, Pages 491-512. Available from: https://www.sciencedirect.com/science/article/pii/B9780123704696000167
Rifampicin Interactions
Rifampicin is a potent CYP3A4 inducer. Hence it will reduce drug levels of Tacrolimus, Cyclosporine, Sirolimus and MMF. This may lead to rejection. It is important to closely monitor drug levels, which may need to be increased 2-5fold. Where possible, Rifabutin is a better option as it is a weaker inducer of CYP3A4 while having similar efficacy to Rifampicin.
Rifampicin has minimal interaction with Azathioprine
Rifampicin increases Prednisolone Clearance, reducing its drug levels. Hence Prednisolone may need to be increased.
Isoniazid Interactions
Isoniazid is a weak CYP inhibitor. Increase in Drug levels of Tacrolimus, Cyclosporine, Sirolimus are usually not significant. There is no interaction with antiproliferatives (MMF and Azathiaprime) However there are increased rates of hepatotoxicity and leucopenia. It is important to monitor for these side-effects.
Reference Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
· Rifampicin and immunosuppressive medications interaction As cyclosporine, tacrolimus, sirolimus, MMF, and prednisone are all effective enzyme inducers, rifampicin can significantly reduce their levels or effects by inducing the cytochrome P450 CYP3A and, to a lesser extent, CYP2C enzymes. · Rifampicin induces CYP3A4 over a number of days, peaking one week after the drug is started. Following the usage of rifampin, it is advised to 3-5 fold increase the dose of CNI or rapamycin while closely monitoring the serum level. · No significant interactions exist between rifampicin and azathioprine. Isoniazid :
Plasma concentrations of isoniazid may be reduced during coadministration with corticosteroids. The mechanism of interaction has not been established, but may involve enhanced hepatic and/or renal elimination of isoniazid .
No interaction with other immunosuppressants( CNI ,mTORi, MMF ) is found
Regularly monitor whole blood cyclosporine levels to ensure optimal therapy. Several drugs have been shown to alter the distribution of cyclosporine by altering hepatic metabolism. Rifampicin is a potent enzyme inducer which increases the clearance of cyclosporine. Rifampicin is a potent CYP3A4 inducer, increasing sirolimus clearance approximately 5.5-fold and decreasing peak concentration (C max ) by 71%. The risk of transplant rejection increases if serum sirolimus levels are not carefully controlled. This interaction should be taken into account when rifampicin or other drugs that affect pregnane X receptor activity are co-administered with mycophenolate mofetil. Rifampicin significantly reduces tacrolimus levels despite several cytochrome P450 inhibitors
References : 1-Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O’Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A.Clin Infect Dis. 2016 Oct 1;63(7):e147-e195. doi: 10.1093/cid/ciw376. Epub 2016 Aug 10.PMID: 27516382 Free PMC article.
Rifampicin
· Its strong enzyme inducer affecting both cytochrome P450 CYP3A and to a lesser extent CYP2C and this led to decrease blood levels of tacrolimus, cyclosporin, sirolimus and MMF. Dose of CNI need to be increased 3-5 folds after starting rifampicin and this effect is delayed in onset usually reach peak at the end of 1st week.
· No effect on azathioprine. INH
· This is controversy, INH is weak enzyme inhibitor with almost no effect in tacrolimus but maybe cyclosporine.
· Regarding MMF, azathioprine levels it has no effect but its hepatotoxicity and myelosuppression effect leads to stoppage of both MMF and azathioprine at 1st 6 weeks after starting treatment.
· Steroids causes reduction of therapeutic level of INH from 20-35% with no proven clinical significance. References
Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin
Tacrolimus : Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.
Cyclosporine : Rifampin, a potent enzyme inducer, has been demonstrated to increase cyclosporine clearance.
Sirolimus : rifampicin is a strong inducer of CYP3A4, it increases the clearance of sirolimus approximately 5.5fold and decreases the maximum concentration (C max ) by 71%.
Azathioprine : The metabolism of Azithromycin can be increased when combined with Rifampicin.
Mycophenolate Mofetil : Long–term rifampin therapy caused a more than twofold reduction in dose–corrected mycophenolic acid (MPA) exposure (dose–interval area under the concentration curve from 0 to 12 hours [AUC0–12]) when administered simultaneously in a heart–lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout.
Prednisone : rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues (area under the plasma concentration time curve) by 66%. The effectiveness of prednisolone may be considerably reduced when rifampicin and prednisolone are used in combination.
———————————————————————
INH cytochrome p 450 inhibitor
Tacrolimus: will decrease the level of Tacrolimus but insignificant Cyclosporine: There were no significant changes in cyclosporine pharmacokinetic parameters including cyclosporine trough levels, total cyclosporine exposure and cyclosporine clearance before and 2 weeks after instituting INH prophylaxis.
Sirolimus Isoniazid can increase the blood levels of sirolimus protein-bound. This may increase side effects such as mouth sores and inflammation, nausea, diarrhea, vomiting, abdominal pain, decreased appetite, increased blood sugar, rash, hair loss, lung or breathing problems, and impaired bone marrow function resulting in low numbers of different types of blood cells.
Azathioprine Common interactions include hepatitis among females and pancytopenia among males.
Mycophenolate mofetil Isoniazid and Mycophenolate mofetil. Common interactions include blood creatinine increased among females and bone marrow toxicity among males.
Prednisone prednisone cause significant decrease in plasma isoniazide consecration by inhanced the renal clearance in slow and rapid inactivator.
BT Ngo, M Pascoe, Delawir Kahn
Transplant Unit, Department of Surgery and Medicine and the Medical Research Council Liver Research Centre, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Drug interaction between mycophenolate mofetil and rifampin: Possible induction of uridine diphosphate-glucuronosyltransferase
CNI: Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel. Thus increases their clearance and reduced blood levels, posing risk of rejection
mTORI: Also increases clearance thus reducing blood levels and increasing risk of rejection
Azathioprine: no interaction
Mycophenolate mofetil: Simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA. Thus it decreases levels of Mycophenolate
Prednisolone: Affects the metabolism and increases steroid non responsiveness.
INTERACTIONS WITH INH:
CNI: cytochrome P450 thus it will increase the levels of tacrolimus, cyclosporine and sirolimus BUT INSIGNIFICANTLY
MMF & AZA : INH causes cytopenia hence will worsen cytopenia caused by MMF and azathioprine when used in combination
Drug interactions Rifampicin
Rifampicin will induce cytochrome P450 and p-glycoprotein thus would cause;
· Low level of CNI(cyclosporine and tacrolimus)
· Low level of mTOR and prednisolone
· NO effect on MMF and AZA. Isoniazid
INH is inhibitor of cytochrome P450 and thus may causes;
· Increases level of CNI and Sirolimus but its effect in not significant.
· Additive effect of Cytopenia when patients are on antimetabolites like MMF and AZA.
1. Tacrolimus, cyclosporine, sirolimus and prednisolone:
Rifampicin is known to induce the hepatic enzyme, CYP3A4.
CYP3A is responsible for up to 90% of cyclosporine, tacrolimus and sirolimus and prednisolone metabolism.
A lower blood level of these drugs is associated with higher risk of graft rejection.
Close monitoring and continuous dose adjustment are highly recommended.
Tow to 5-fold increments in the daily dose of cyclosporine, tacro limus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range
2. MMF: clinically relevant interaction between rifampicine and MMF. Long term Rifampicine therapy causes more than 2 fold reduction in dose – corrected MPA exposure dose. Failure to clinically recognize drug interaction could clinically to MPA underexposure and loss of clinical efficacy.
3. Azathioprine: no interaction with rifampicine
INH interaction with
1. CNI, zathioprine and MMF: No interaction
2. Prednisolone: Prednisolone decrease the level of INH due to decreased renal clearance of INH.
References:
1. T. Ngo, M. Pascoe, Delawir Kahn, Drug Interaction between Rifampicin and Sirolimus in Transplant Patients
2. Drug interaction between MMF and rifampicine.Clinical Pharmcology &Therapeutics (2005) 78, 81-88
3. GR Sharma , effect Agents of prednisolone and rifampicine on INH metabolism in slow and rapid inactivators of INH, Antimicrob Chemother 1980 Nov, 18(5)661-666
Drug interactions
Rifampicin is a potent cytochrome P 450 and p-glycoprotein inducer hence will reduce the levels of CNI and MTOR inhibitors. It also interferes with the metabolism of corticosteroids.Thus will lead to low levels of cyclosporine, tacrolimus, sirolimus and prednisolone.
Rifampicin and antimetabolites (MMF and azathioprine) doesn’t affect its metabolism whoever concomitant use may worsen adverse events like cytopenias.
Isoniazid is an inhibitor of cytochrome P450 thus it will increase the levels of tacrolimus, cyclosporine and sirolimus however this effect is not significant.
Isoniazid also cause cytopenias hence will worsen cytopenia caused by MMF and azathioprine if given concurrently.
References
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, Gina Ciolan, Costin Gîngu, Ioanel Sinescu and Cătălin Baston.
RIFAMPICIN is a potent inducer of several drug-metabolizing enzymes as well as P-glycoprotein (P-gp) multidrug efflux transporters, which can lead to significant reductions in concentrations and therapeutic failure of other drugs. Drug interactions result from the ability of rifampin to induce cytochrome P450 CYP3A metabolism (and to a lesser extent CYP2C) and glucuronidation, thereby accelerating drug excretion. Rifampin also increases intestinal P-gp mediated drug efflux, thereby reducing gastrointestinal absorption of drugs that are P-gp substrates.
Thus RIFAMPICIN decreases levels of TACROLIMUS and to overcome that the dose of tacrolimus should be increased to at least three to five folds. Decreases level CICLOSPORIN AND SIROLIMUS
Azathioprine No effect
MYCOPHENOLATE
The interaction is less pronounced however long term use can lead to lower MMF levels
PREDNISONE
Overall, rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues (area under the plasma concentration time curve) by 66%. The effectiveness of prednisolone may be considerably reduced when rifampicin and prednisolone are used in combination.
INH
it can increase level of tacrolimus and ciclosporin and Sirolimus leading to nephrotoxicity
No effect on AZA and MMF
it can increases bone marrow suppressive effect when used in combination with AZA
-Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, and enhance immunosuppression metabolization. Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and increases glucocorticoids metabolization, and azathioprin which increases the risk of rejection.
-Therefore:
Calcineurin and mTOR inhibitors levels should be closely monitored
The dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold.
glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. [1]
MMF:
Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure when used simultaneously.
The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA. [2]
References:
1- Sorohan BM et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. 2- Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther. 2005 Jul;78(1):81-8
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
Rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus).
Rifampicin usage decrease the levels of mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .
Rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Tacrolimus : Rifampicin decrease level of tacrolimus,
Cyclosporine: Rifampicin decrese level of cyclosporine
Sirolimus : Rifampicin decrese level of sirolimus .
Azathioprine : no effect.
Mycophenolate Mofetil : no effect
Prednisone :Rifampicin affect glucocorticoids metabolization (may increase level ) Isoniazid
INH inhibit CP450 3A4 inhibitor and monoamine oxidases.
Therefore, it will increase the level of CNI, mTOR inhibitors.
Steroids decreases the level of INH.
INH has significant adverse effect cytopenia and hepatotoxicity, co-administration with antimetabolites may augment this effect.
Tacrolimus: INH increase level of tacrolimus.
Cyclosporine: INH increase level of cyclosporine .
Sirolimus: INH increase level of sirolimus
Azathioprine: no change .
Mycophenolate Mofetil: no change.
Prednisone: may decrease level of INH.
REFERENCES
1.Subramanian, A.K.; Theodoropoulos, N.M. Mycobacterium Tuberculosis Infections in Solid Organ Transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin. Transplant. 2019, 33, e13513.
2. Meije, Y.; Piersimoni, C.; Torre-Cisneros, J.; Dilektasli, A.G.; Aguado, J.M. Mycobacterial Infections in Solid Organ Transplant Recipients. Clin. Microbiol. Infect. 2014, 20 (Suppl. 7), 89–101
3.Aguado, J.M.; Torre-Cisneros, J.; Fortún, J.; Benito, N.; Meije, Y.; Doblas, A.; Muñoz, P. Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin. Infect. Dis. 2009, 48, 1276–1284.
4.Bolt, H.M. Rifampicin, a Keystone Inducer of Drug Metabolism: From Herbert Remmer’s Pioneering Ideas to Modern Concepts. Drug Metab. Rev. 2004, 36, 497–509.
5.Nakada, Y.; Yamamoto, I.; Kobayashi, A.; Mafune, A.; Yamakawa, T.; Matsuo, N.; Tanno, Y.; Ohkido, I.; Yamamoto, H.; Yokoyama, K.; et al. Acute Vascular Rejection during Antituberculosis Therapy in a Kidney Transplant Patient. Nephrology 2014, 19 (Suppl. 3), 27–30.
6. Chuang, H.-W.; Chung, T.-L.; Lee, P.-T.; Wang, J.-S. Acute Antibody-Mediated Rejection with Graft Loss during Anti-Tuberculosis Therapy in Kidney Transplantation. Kaohsiung J. Med. Sci. 2015, 31, 437–439. Chenhsu, R.Y.; Loong, C.C.; Chou, M.H.; Lin, M.F.; Yang, W.C. Renal Allograft Dysfunction Associated with Rifampin-Tacrolimus Interaction. Ann. Pharmacother. 2000, 34, 27–31.
– Rifampin is a potent inducer of cytochrome P450 CYP3A metabolism (and to a lesser extent CYP2C) and glucuronidation and in doing so accelerates drug excretion.
– Rifampin also increases intestinal P-glycoprotein (P-gp) mediated multidrug efflux transporter and by such means reduces GI absorption of drugs that are P-gp substrates like tacrolimus.
– Tacrolimus is metabolized by CYP3A5 and CYP3A4 in the liver and small intestine.
– Rifampin induces both intestinal and hepatic metabolism of tacrolimus through induction of CYP3A4 and p-glycoprotein in both the liver and small bowel.
– the serum concentration of tacrolimus can increase when it is co-administered with INH since INH alters tacrolimus metabolism resulting in increased tacrolimus trough levels
– Rifampin is a potent inducer of cytochrome P450 CYP3A metabolism (and to a lesser extent CYP2C) and glucuronidation and in doing so accelerates drug excretion.
– Rifampin also increases intestinal P-glycoprotein (P-gp) mediated multidrug efflux transporter and by such means reduces GI absorption of drugs that are P-gp substrates like tacrolimus.
– Tacrolimus is metabolized by CYP3A5 and CYP3A4 in the liver and small intestine.
– Rifampin induces both intestinal and hepatic metabolism of tacrolimus through induction of CYP3A4 and p-glycoprotein in both the liver and small bowel.
– Metabolism of cyclosporine can be decreased when co-administered with INH
– CYP3A is essential for up to 90% of CNI (tacrolimus, cyclosporine) and mTORi (sirolimus) metabolism.
– Rifampicin is a potent inducer of CYP3A4, hence it increases the clearance of sirolimus by ~5.5fold and decreases the Cmax (maximum concentration) by 71%. This in effect increases the risk of graft rejection if the sirolimus dose is not adjusted accordingly.
– INH alters sirolimus drug metabolism resulting in an increase in the sirolimus trough levels
Azathioprine
– Rifampicin increases the metabolism of azathioprine
– Metabolism of azathioprine can be decreased when co-administered with INH
– MMF is a cornerstone immunosuppressive agent in SOT.
– Rifampicin induces the expression of a number of drug metabolism-related genes involved in cytochromes (CYP3A4), multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), monoamine oxidases, glutathione S-transferases, uridine phosphate-glucuronosyltransferases (UGT). Drugs depending on these enzymes for their metabolism are prone to drug interactions with rifampicin when administered together.
– Rifampin use simultaneously induces renal, hepatic and GI UGT and organic anion transporters leading to functional inhibition of enterohepatic recirculation of MMF.
– Metabolism of MMF can be decreased when co-administered with INH
– Rifampicin is an inducer of enzymes responsible for hepatic drug metabolism.
– Rifampicin increases the plasma clearance of prednisone by
~45% and reduces the amount of drug available to the tissues (i.e., AUC) by 66%.
– this therefore implies that the effectiveness of prednisone is reduced when it is co-administered with rifampicin
– INH alters metabolism of prednisone hence increasing the prednisone levels
– Prednisone decreases plasma INH concentrations in both slow and rapid inactivators
– Prednisone increases the rate of INH acetylation in slow inactivators only
– Prednisone enhances renal clearance of INH in both slow and rapid inactivators
References
1. Hebert MF, Fisher RM, Marsh CL, Dressler D, Bekersky I. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. Journal of clinical pharmacology. 1999 Jan;39(1):91-6. PubMed PMID: 9987705. Epub 1999/02/13. eng.
2. Charfi R, Ben Sassi M, Gaïes E, Bacha M, Jebabli N, El Jebari H, et al. Early interaction between tacrolimus and rifampin. La Tunisie medicale. 2019 May;97(5):722-5. PubMed PMID: 31729747. Epub 2019/11/16. eng.
3. Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin, rifabutin, and rifapentine drug interactions. Current medical research and opinion. 2013 Jan;29(1):1-12. PubMed PMID: 23136913. Epub 2012/11/10. eng.
4. Sehgal SN. Rapamune (Sirolimus, rapamycin): an overview and mechanism of action. Therapeutic drug monitoring. 1995 Dec;17(6):660-5. PubMed PMID: 8588237. Epub 1995/12/01. eng.
5. Ngo B, Pascoe M, Kahn D. Drug interaction between rifampicin and sirolimus in transplant patients. Saudi Journal of Kidney Diseases and Transplantation. 2011 January 1, 2011;22(1):112-5.
6. Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clinical pharmacology and therapeutics. 2005 Jul;78(1):81-8. PubMed PMID: 16003296. Epub 2005/07/09. eng.
7. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. British medical journal (Clinical research ed). 1983 Mar 19;286(6369):923-5. PubMed PMID: 6403136. Pubmed Central PMCID: PMC1547305. Epub 1983/03/19. eng.
8. Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrobial agents and chemotherapy. 1980 Nov;18(5):661-6. PubMed PMID: 7447424. Pubmed Central PMCID: PMC284072. Epub 1980/11/01. eng. https://www.webmd.com/interaction-checker/default.htm https://go.drugbank.com/drugs/DB00951
Rifampicin is a potent cytochrome CYP3A enzyme inducer, so it tends to reduce the level of drugs metabolized by this enzyme.
Tacrolimus Rifampicin reduces the level of Tacrolimus (severe interaction). INH doesn’t interact with Tacrolimus.
Cyclosporin Rifampicin reduces the level of Ciclosporin (severe interaction). INH doesn’t interact with Ciclosporin.
Sirolimus Rifampicin reduces the level of Sirolimus (severe interaction). INH doesn’t interact with Sirolimus.
Azathioprine Rifampicin doesn’t have interactions with azathioprine. INH doesn’t have interactions with Azathioprine. However, INH side effects include hepatotoxicity and leucopenia which can exacerbates side effects of Azathioprine.
Mycophenolate Mofetil Rifampicin reduces the level of Mycophenolate (severe interaction). INH doesn’t interact with Mycophenolate. However, INH side effects include hepatotoxicity and leucopenia which can exacerbates side effects of Mycophenolate.
Prednisone Rifampicin is predicted to decrease the exposure to Prednisolone. Manufacturer advises monitor and adjust dose. (moderate severity).
As a strong CYP3A4 inducer, Rifampicin decreases the serum concentration of Sirolimus, Tacrolimus and cyclosporin, requiring increasing the dose.
on the other hand, INH is a weak CYP3A4 inhibitor that increases cyclosporin, tacrolimus and cyclosporin levels.
CycloSPORINE may enhance the neuroexcitatory and or seizure-potentiating effect of Prednisolone.
Rifampicin may decrease serum concentrations of the active metabolites of Mycophenolate, Specifically, mycophenolic acid (MPA), conc. Maybe decrease.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
Rifampicin :
Rifampicin, a potent inducer of cytochrome P450 3A4 .
rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus).Rifampicin reduce the level of prednisolone and increase its clearance.
when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. Additionally, after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target .
MMF and AZA : no interaction.
INH : is an enzyme inhibitor
INH increase the level of Tacrolimus and sirolimus.
INH has no interaction with cyclosporine, MMF,AZA.
INH increase the level of prednisolone, and prednisolone can decrease the concentration of INH.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications? Tacrolimus Cyclosporine Sirolimus Azathioprine Mycophenolate Mofetil Prednisone
Rifampicin
Rifampicin is enzyme inducer CYP 3A4
It will reduce the drug levels of –
· Tacrolimus
· Cyclosporine
· Sirolimus
· MMF
· No interaction with Azathioprine
· It can reduce levels of prednisolone
Isoniazid- INH
It is inhibitor of CYP 3A4
It will increase levels of tacrolimus and sirolimus
No interaction with Cyclosporine, azathioprime and MMF
INH will increase the level of Prednisolone
Lwin PW, Htun YY, Myint AK, Swe HK. Posttransplantation tuberculosis management in terms of immunosuppressant cost: a case report in Myanmar. Korean J Transplant. 2021 Mar 31;35(1):48-52
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
· Tacrolimus
· Cyclosporine
· Sirolimus
· Azathioprine
· Mycophenolate Mofetil
· Prednisone
Rifampicin:
The Rifamycins (Rifampicin and Rifabutin) are strong inducers of enzyme CYP3A4. They are associated with increased metabolism, and hence reduced drug levels of calcineurin inhibitors (cyclosporin and Tacrolimus) and mTOR inhibitors (sirolimus and everolimus) thereby warranting an increase in the doses of these medications (1). Hence dose of Cyclosporin, Tacrolimus, and sirolimus needs to be increased at time of initiation of rifampicin (dose increase required in range of 2-5 times, even upto 10 times), and regular monitoring of trough levels is required. At time of discontinuing rifampicin, the doses need to be reduced accordingly. Rifabutin is a less potent enzyme inducer, hence the increase in dose required would be lower as compared to rifampicin use.
Effect of Rifampicin on Mycophenolate mofetil (MMF) is less pronounced, but nevertheless is associated with lower MMF levels (induction of mycophenolic acid glucuronidation via uridine diphosphate-glucuronosyltransferase, and reduced enterohepatic recirculation).Tthis combination should be avoided as per the manufacturer (1,2).
There is no discernible effect of rifampicin use on azathioprine.
Rifampicin use also reduces the levels of steroids (CYP3A4 induction), hence the dose of steroids should be increased to 2 -times (1,3).
Isoniazid:
Although isoniazid is a CYP3A4 enzyme inhibitor, leading to increased levels of cyclosporin, tacrolimus, everolimus, and sirolimus, the effect on these drugs is not significant (1). There is no effect of isoniazid on MMF and azathioprine. But concomitant use of isoniazid with antimetabolites can pronounce the side effects like leukopenias. Use of Steroids and Isoniazid together is associated with reduced levels of isoniazid (4).
References:
1. Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13510. doi: 10.1111/ctr.13510. Epub 2019 Apr 23. PMID: 30817021.
2. Naesens M, Kuypers DR, Streit F, Armstrong VW, Oellerich M, Verbeke K, Vanrenterghem Y. Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients. Clin Pharmacol Ther. 2006 Nov;80(5):509-21. doi: 10.1016/j.clpt.2006.08.002. PMID: 17112807.
3. Monostory K. Metabolic Drug Interactions with Immunosuppressants. Organ Donation and Transplantation – Current Status and Future Challenges [Internet]. 2018 Jul 25; Available from: http://dx.doi.org/10.5772/intechopen.74524
4. Yew WW. Clinically significant interactions with drugs used in the treatment of tuberculosis. Drug Saf. 2002;25(2):111-33. doi: 10.2165/00002018-200225020-00005. PMID: 11888353.
Although isoniazid is a CYP3A4 enzyme inhibitor, leading to increased levels of cyclosporin, tacrolimus, everolimus, and sirolimus, the effect on these drugs is insignificant. There is no effect of isoniazid on MMF and azathioprine. But concomitant use of isoniazid with antimetabolites can pronounce the side effects like leukopenias. Steroids and Isoniazid are associated with reduced levels of isoniazid.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
INH (Isoniazid) (It is an enzyme inhibitor – CYP3A4)((Decrease Metabolism of):
-INH => will increase the levels of tacrolimus.
-Cyclosporine => No interaction
-INH => will increase the levels of sirolimus
-AZA=> No interaction
-MMF => No interaction
-Prednisone=> INH will increase the level of prednisone and prednisone can reduce the drug concentration of INH
Rifampicin: (It is an enzyme inducer – CYP3A4)(increase Metabolism of):
– Rifampicin => will reduce the levels of tacrolimus
-Rifampicin => will reduce the level of cyclosporine
-Rifampicin => will reduce the level of sirolimus
-AZA => No interaction
-MMF => No interaction
– Rifampicin will reduce the levels of prednisone(Rifampicin increases prednisolone clearance by around 45% and reduce the amount of drug available to the tissues by around 66%)
References:
*Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
*Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
[
*Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
-Rifampicin leads to expression of drug metabolism-related genes involved in multidrug resistance ;P-glycoprotein &multidrug resistance proteins 1 and 2.Also,it induces:
. Cytochrome P450 [CYP] 3A4).
.Uridine diphosphate-glucuronosyltransferases.
. Monoamine oxidases.
. Glutathione S -transferases.
Drugs involving these enzymes in their metabolism are vulnerable to drug-drug interactions when used with rifampin.
– Rifampicin decreases the levels of CNI, (mTOR) inhibitors , and affects glucocorticoids metabolism; increasing clearance by 49% and tissue availability by 66%. INH through inhibiting CP450 3A4 inhibitor and monoamine oxidases, will increase the level of CNI, mTOR inhibitors.
Steroids decrease INH level with unclear mechanism.
INH has hepatotoxicity and cytopenia, so its use with antimetabolites may aggravate these effects.
One of the challenges of treating TB in KTRs is drug–drug interactions:
1. Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
2. Specifically, rifampicin usage decreases the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection(1).
3. INH will increase the level effect of CNIs and mTORi by affecting hepatic/intestinal enzyme CYP3A4 metabolism(2).
4. Plasma concentrations of isoniazid may be reduced during coadministration with corticosteroids. The mechanism of interaction has not been established, but may involve enhanced hepatic and/or renal elimination of isoniazid. In a study of 26 patients with tuberculosis given isoniazid 10 mg/kg/day, investigators reported a 23% reduction in plasma isoniazid concentrations for slow acetylators and a 38% reduction for rapid acetylators following the administration of a single 20 mg dose of prednisolone. The clinical significance of this potential interaction is unknown. Prednisolone did not appear to alter the clinical response to isoniazid treatment in the study. Nonetheless, it may be advisable to monitor patient response to isoniazid more closely during concomitant corticosteroid therapy and adjust the isoniazid dosage if necessary(3,4).
Drug-Drug interaction(Rif & INH plus the followings)(2,5) Tacrolimus and Cyclosporine: a) The coadministration with rifamycins, particularly rifampin, may decrease the blood concentrations and pharmacologic effects of cyclosporine and tacrolimus. The mechanism probably involves reduced absorption as well as accelerated clearance of CNIs due to induction of both intestinal P-glycoprotein drug efflux pumps and hepatic/intestinal CYP450 3A4 isoenzymes by rifamycins. b) Isoniazid may decrease serum cyclosporine and tacrolimus concentrations. The mechanism is induction of hepatic CYP450 3A4 metabolism by isoniazid. 5. Sirolimus: a) Coadministration with rifampicin, potent inducers of CYP450 3A4 and/or P-glycoprotein may significantly decrease the plasma concentrations and pharmacologic effects of sirolimus. The mechanism probably involves reduced absorption as well as accelerated clearance of sirolimus due to induction of both intestinal P-glycoprotein drug efflux transporter and hepatic/intestinal CYP450 3A4 isoenzymes. b) INH will increase the level or effect of sirolimus by affecting hepatic/ intestinal enzyme CYP3A4 metabolism. 6. Azathioprine a) No interactions were found between the drug and rifampicin. b) No interactions were found between the drug and INH. 7. Mycophenolate Mofetil: a) Coadministration with rifampin may decrease the plasma concentrations of mycophenolic acid (MPA). The mechanism is thought to involve induction of MPA glucuronidation via gastrointestinal and hepatic uridine diphosphate glucuronosyltransferase (UGT) isozymes and reduction of enterohepatic recirculation of MPA metabolites secondary to competitive inhibition of multidrug resistance-associated protein 2 (MRP2)-mediated biliary excretion by rifampin. b) No interactions were found between the drug and INH.
8. Prednisone
a) Rifampicin may induce the hepatic metabolism of corticosteroids, possibly reducing their therapeutic effect. The elimination half-life of corticosteroids has been shown to be reduced by up to 45% when rifampin is coadministered.
b) Plasma concentrations of isoniazid may be reduced during coadministration with corticosteroids. The mechanism of interaction has not been established, but may involve enhanced hepatic and/or renal elimination of isoniazid.
References
1. Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
2. Medscape online.
3. Sarma G, Kailasam S, Nair NG, Narayana AS, Tripathy SP “Effect of prednisonlone and refampin on isoniazid metabolism in slow and rapid inactivators of isoniazid.” Antimicrob Agents Chemother 18 (1980): 661-6
4. Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, MacIntyre I, Park BK “Effect of isoniazid on vitamin D metabolism and hepatic monooxygenase activity.” Clin Pharmacol Ther 30 (1981): 363-7
Drug-induced neutropenia can occur in association with anti-TB .
The incidence rate of agranulocytosis due to anti-tuberculosis drugs was estimated at 0.06% . In the context of anti-tuberculosis therapy, neutropenia is recognized as being most frequently happening due to isoniazid , but it can be related to rifampicin , ethambutol and streptomycin prescription .
It is obvious that the haematological side effects of anti-TB ( agranulocytosis and neutropenia) can be aggravated by the adverse effects of anti metabolites( AZA and MMF).
Reference CASE REPORT Leukopenia Induced by Anti-Tuberculosis Treatment Belloumi N, Ben Bdira B, Bachouche I, Kacem M, Chermiti Ben Abdallah F and Fenniche S DOI:10.23937/2378-3516/1410093
Anti-TB drugs and their side effects
First line anti MTB includes, rifampicin, INH , pyrazinamide, ethambutol
The mean concern about medications in general including anti-MBT drugs includes efficacy, safety, drug-drug interaction, side effects, toxicity, cost
Use of anti-TB medication after SOT there is concern about the drug interactions with other immunosuppressive medications in particular CNI ( Tacrolimus, cyclosporine ), m TOR inhibitors like sirolimus and everolimus, antimetabolites ( azathioprine and MMF ), Steroids RIFAMPICIN
Rifampicin considers the first-line anti-TB with high potency for sterilization of mycobacteria through its bactericidal effects inhibit protein synthesis by blocking mRNA transcription and synthesis; hepatically metabolized. But there is concern about its hepatotoxicity as it acts as an enzyme inducer through the cytochrome 450, CYP3A4, and rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. and can reduce the level of CNI, sirolimus, and everolimus even to undetectable levels so we need to increase the dose of tacrolimus or Cyclosporine by 3-5 folds ( sometimes will give TID dose ) with close monitoring by trough level, also need frequent LFT monitoring for transaminitis weekly in the first two months then every month, rifabutin as an alternative can be used and it’s more tolerated compared to rifampicin, rifabutin has a lower cytochrome inducer effect Dose: rifampicin 600 mg/d; rifabutin 300 mg/d. Sirolimus follows the same for CNI and needs dose adjustment with frequent monitoring
.
No interaction with azathioprine,
MMF and rifampicin lead to reduced the level of MMF due to interaction with enterohepatic circulation.
INH Isoniazid and rifamycins can cause drug-induced hepatitis, and the previously used combination of rifampicin/pyrazinamide can cause severe liver toxicity(3). So needs close monitoring twice weekly in the first two weeks then weekly in the first two months, consider discontinuation if liver enzymes increased by 5 folds from baseline.
INH and steroids prednisolone caused a significant decrease in the plasma isoniazid concentrations in both slow and rapid inactivators (2).due to increased renal clearance of isoniazid in both slow and rapid inactivators and augmented the rate of acetylation of isoniazid in slow inactivators but concomitant administration of rifampin had considerably modified the prednisolone effect on the disposition of isoniazid.
MMF and azathioprine , sirolimus , CNI ( NONE ) .
References
1. Pennington KM, Kennedy CC, Chandra S, Lauzardo M, Brito MO, Griffith DE, Seaworth BJ, Escalante P. Management and diagnosis of tuberculosis in solid organ transplant candidates and recipients: Expert survey and updated review. J Clin Tuberc Other Mycobact Dis. 2018 Apr 10;11:37-46.
2. Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother. 1980 Nov;18(5):661-6
3. . Aguado JM, Torre-Cisneros J, Fortun J. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish society of infectious diseases and clinical microbiology. Clin Infect Dis. 2009;48(9):1276–1284. [PubMed] [Google Scholar]
Van Leeuwen RF et, al. Potential drug interactions and duplicate prescriptions among ambulatory cancer patients: a prevalence study using an advanced screening method. BMC Cancer. 2010 Dec 13;10:679.
Drug interactions. (IBM) Merative Micromedex: Available from: ww.micromedexsolutions.com
⭐ Rifampin is an enzyme inducer of CYT P 3A4 that is important in metabolism of CNI and mTORi , so it’s concomitant use decrease trough level of cyclosporin, tacrolimus and sirolimus, so increasing their dose by 3-5 folds is indicated to decrease risk of rejection.
Also it decrease the concentration of steroids by 45%, so doubling of steroid dose is usually required to minimize risk of rejection.
However, it inhibits the entro-hepatic circulation so increase the concentration of MMF
⭐ INH is enzyme inhibitors so may increase concentration of CNI and mTORi
⭐ INH can cause myelosuppression, so it can augment the adverse effects of MMF when used together as causing leukopenia.
Drug interactions between Rifampicin against immunosuppressants medication
Tacrolimus – reduction in the level
Cyclosporine – reduction in the level
Sirolimus – reduction in the level
Azathioprine – no effect
Mycophenolate Mofetil – Mild increase in the level
Prednisone – reduce the level.
Rifampicin is a potent Cyt 450 inducer so enhances the metabolism of the above medications.
Drug level should be monitored closely, and the dose should be increased 2-3 folds to avoid graft rejection as per drug levels.
Drug interactions between INH against immunosuppressants medication
INH against TAC/CyA/SIR/AZA/MMF; No major drug interaction.
References
[1] Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
[2] Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
[3] Gervasini G, Benítez J, Carrillo JA. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. European Journal of Clinical Pharmacology. 2010;66:755-774. DOI: 10.1007/s00228-010-0857-7
All the rifamycins are strong inducers of CYP3A4 Both rifampicin and rifabutin decrease the plasma levels of calcineurin and mTOR inhibitors, leading to acute graft rejection
Tacrolimus – reduce the level
Cyclosporine – reduce the level
Sirolimus – reduce the level
Azathioprine – no effecet
Mycophenolate Mofetil – increases the level
Prednisone – reduce the level
Mycophenolate is metabolized into mycophenolic acid, which undergoes glucuronidation by uridine diphosphate glucuronosyltransferases (UGTs) in the liver, kidney, and intestine to its inactive metabolite (7-O-glucuronide). Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by UGTs and reduces enterohepatic recirculation and absorption of mycophenolic acid. Also one metabolite of MMF, acyl-glucuronide, gets accumulated and attains higher blood level in presence of rifampicin, which may increase the toxicity or adverse effect
Isoniazid and ethambutol do not seem to interact with immunosuppressive agents.
Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
Rifampicin:
o A potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization
o Decreases the levels of CNIs (cyclosporine, tacrolimus), the mTOR inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization (also reduce the level), which increases the risk of rejection
o When a rifampicin-based regimen is used, CNIs and mTOR inhibitors levels should be closely monitored, the dose of CNIs and mTOR inhibitor should be increased between 3-5-folds and the glucocorticoid dose should be doubled during treatment and adjusted thereafter
o After the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target
o Rifampicin also reduce the concentration of active mycophenolate metabolite
o No direct interaction of rifampicin with azathioprine
INH:
There is no direct interaction with the above immunosuppressants but increase the risk of hepatotoxicity, neurotoxcity, and cytopenia that caused by other anti-tuberculous drugs
References
1. Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris ,ca˘, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
2. The Renal Drug Handbook, 5th edition, 2019.
Rifampicin, induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2). – Cytochromes (cytochrome P450 [CYP] 3A4). – Uridine diphosphate-glucuronosyltransferases. – Monoamine oxidases. – Glutathione S -transferases.
Drugs that depend on these enzymes for their metabolism are prone to drug interactions when co-administered with rifampin.
– Rifampicin Potent inducer of cytochrome P450 3A4 and P-glycoprotein: its usage decrease the levels of CNI (cyclosporine, tacrolimus), (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection.
-Rifampin induce renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA that reduce drug exposure in heart-lung transplant recipient. Isoniazid INH inhibit CP450 3A4 inhibitor and monoamine oxidases. Therefore, it will increase the level of CNI, mTOR inhibitors. Steroids decreases the level of INH, mechanism is unclear. INH has significant adverse effect cytopenia and hepatotoxicity, co-administration with antimetabolites may augment this effect.
References: Sparkes, T, Lemonovich, TL. Interactions between anti-infective agents and immunosuppressants—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13510. https://doi.org/10.1111/ctr.13510
Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther. 2005 Jul;78(1):81-8. doi: 10.1016/j.clpt.2005.03.004. PMID: 16003296.
Excellent response. You mentioned previously Referred in case 1 to difference between Rifampicin and Rifabutin which is worth mentioning here because of the differential effect on Tacrolimus with similar antibiotic effect.
This is usually forgotten is the impact of Rifampicin on prednisolone. Rifampicin increases prednisolone clearance by around 45% and reduce the amount of drug available to the tissues by around 66%
Rifabutin has similar efficacy to Rifampin, both drugs induce CP450 3A4, but Rifabutin is much less potent enzyme inducer, which make achieving therapeutic level of IS easier than Rifampin.
INH : it is enzyme inhibitors as it inhibits CYP3A4 , so increases the level of Tacrolimus, sirolimus prednisone, while it will not affect cyclosporine, MMF, AZA
Using INH with anti metabolite with aggravate cytopenia
Rifampicin: is a potent enzyme inducer as it activates CYP3A4 , so it decreases level of Tacrolimus, cyclosporine, and sirolimus with no effect on AZA and MMF
References:
*Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin: is a potent enzyme inducer of CYP3A4
Cyclosporine = CYP3A4 Inducers (Strong) may decrease the serum concentration of Cyclosporin. Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Risk D: Consider therapy modification.
Tacrolimus = CYP3A4 Inducers (Strong) may decrease the serum concentration of Tacrolimus (Systemic). Management: Monitor for decreased tacrolimus concentrations and effects when combined with strong CYP3A4 inducers. Tacrolimus dose increases will likely be needed during concomitant use. Risk D: Consider therapy modification
Sirolimus = (Protein Bound) CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. Risk X: Avoid combination.
Mycophenolate = RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased. Management: Avoid concurrent use of rifampin and mycophenolate when possible. If used together, closely monitor mycophenolic acid levels and clinical response. Mycophenolate doses may need to be increased. Risk D: Consider therapy modification.
Azathioprine = The metabolism of Azathioprine can be increased when combined with Rifampicin.
Prednisone = CYP3A4 Inducers (Strong) may decrease the serum concentration of Prednisone. Risk C: Monitor therapy.
Rifampicin causes a profound reduction in the serum levels of tacrolimus, cyclosporine, sirolimus, everolimus, and corticosteroids, thus high risk of graft rejection, so the dose should be increased 3-5 folds, with continuous blood level monitoring.
Isoniazid (INH): inhibits the cytochrome P450 system
Cyclosporine = CYP3A4 Inhibitors (Weak) may increase the serum concentration of Cyclosporin. Risk C: Monitor therapy.
Tacrolimus = CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy.
Sirolimus = CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus. Risk C: Monitor therapy
Mycophenolate = No effect on its level.
Azathioprine = No data of interaction.
Prednisone = May decrease the serum concentration of Isoniazid. Risk C: Monitor therapy
References: (1) Aguado JM, Silva JT, Samanta P, Singh N. Tuberculosis and Transplantation. Microbiol Spectr. 2016 Nov;4(6). doi: 10.1128/microbiolspec.TNMI7-0005-2016. PMID: 27809952. (2) Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother. 1980 Nov;18(5):661-6. doi: 10.1128/AAC.18.5.661. PMID: 7447424; PMCID: PMC284072. (3) UpToDate and Micromedex.
Thank you Dr Mohammad Alshaikh Hasan.
Well done. I could not understand the classification of Risk grading and difference between risk C,D, and X.
If used together, closely monitor mycophenolic acid levels and clinical response. I’m not sure that this is a routine practice for monitoring Mycophenolic acid level when combined with Rifampicin.
Therefore it’s worth mentioning Rifabutin as a replacement for Rifampicin with less enzyme inducer effect compared to Rifampicin.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?Rifampcin and INH are both enzyme inducer for cytochromep450isoenzyme cyp3A4 can reduce BOTH CNI (TAC&cyclosporin ) and mTOR(sirolimus)
so need to increase CNI 3 to 5fold this takes several days to occur and peaks with a weak and also with mTOR
Rifampicin has been associated with rejection if combined with CNI or mTOR.
no interaction between INH& Rifampicin and Azathioprine
MMF reduce by rifampicin although MMF in the active T.B reduce or hold in the first 6 weeks
prednisolone reduce by rifampicin although this has been less well characterized
reference
UpToDate
Rifampicin is a potent enzyme inducer of CYP3A4.
Rifampicin causes marked reduction in their serum levels tacrolimus, cyclosporine, m TOR and steroid.no interaction with azathioprine.
INH inhibits the cytochrome P450 system and acts as a mild monoamine oxidase inhibitor (MAO-I)
INH will increase the level or effect of tacrolimus and Sirolimus.
no effect on cyclosporin, azathioprine, MMF
I- Drug interaction between rifampicine and immune suppression: `
Rifampicine is a potent enzyme inducer of CYP3A4 which is the main enzyme involved in metabolism of tacrolimus , m TOR , MMF and steroid . so combination of those drugs with Rifampicine causes marked reduction in their serum levels , thus frequent trough drug level monitoring is required from starting treatment with rifampicine and for 2 weeks after stopping it,as its effect on CYP3A4 continue for 2 weeks after its sessation. A;so , the dose will need to be increase up to (2-5) folds II- INH :inhibits both the cytochrome P450 and monoamine oxidase systems , so it will increase the level of tacrolimus and Sirolimus . But no interaction between INH and cyclosporine, azathioprine and mycophenolate
You have implied in your first paragraph that MMF levels might decrease when commenced on Rifampicin. However, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Rifampin should be used with caution due to significant interactions between this class of drug and the calcineurin inhibitors and rapamycin (sirolimus). The rifamycins (especially rifampin) reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, and the combination of a rifamycin with these drugs has been associated with the development of rejection . Rifamycins also reduce levels of glucocorticoids, although this has been less well characterized ●If rifampin is used, the dose of the calcineurin inhibitor or rapamycin should be increased approximately three- to fivefold, and serum concentrations should be monitored CYP3A4 induction by rifampin takes several days to occur, usually peaks within a week, and lasts for days to weeks
**the interaction of the anti-tuberculous drugs (Rifampicin and INH) Rifampicin and Isoniazid (INT) (CYP3A4 Inducers (Strong))
may decrease the serum concentration of Tacrolimus -Cyclosporine – Sirolimus
Risk RatingD: Consider therapy modification
Severity Major Reliability Rating Good Patient Management Monitor closely for reduced Tacrolimus -Cyclosporine – Sirolimus
concentrations when combined with strong CYP3A4 inducers.
Tacrolimus -Cyclosporine – Sirolimus DOSES increases will likely be required to maintain adequate serum concentrations.
**Azathioprine-(Rifampicin and INH) No interactions of Risk Level A or greater identified
**Mycophenolate / RifAMPin Risk Rating D: Consider therapy modification
RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased. Severity Major Reliability Rating Good Patient Management Avoid concurrent use of rifampin and mycophenolate when possible. If used together, closely monitor mycophenolic acid levels and clinical response. Mycophenolate doses may need to be increased.
**(MMF-INH) No interactions of Risk Level A or greater identified.
**PredniSONE / (Rifampicin and INH) Risk Rating C: Monitor therapy
CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE. Severity Moderate Reliability Rating Excellent Patient Management Monitor for decreased prednisone effects if combined with a strong CYP3A4 inducer. Increases in prednisone dose may be required to maintain steroid effectiveness.
You mention that MMF levels might decrease when commenced on Rifampicin. I have not heard that.
However, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
–Rifampicin is a strong inducer of CYTP3A4 increasing metabolism of CNI as Tac and cyclosporine, and mTOR inhibitors as Sirolimus , and mycophenolate mofetil and prednisolone .
For cyclosporine , Rifampicin also decreases the absorption of cyclosporine by inducing its metabolism by gut wall.
For MMF, Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by uridine diphosphate glucuronosyltransferases (UGTs) and reduces enterohepatic recirculation and absorption of mycophenolic acid also one metabolite of MMF, acyl-glucuronide, gets accumulates with rifampicin, which may increase the toxicity or adverse effects.
For azathioprine there was no interaction noted with Rifampicin
–INH inhibits the cytochrome P450 system and acts as a mild monoamine oxidase inhibitor (MAO-I)
INH will increase the level or effect of tacrolimus and Sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
INH did not show interaction with cyclosporine, azathioprine and mycophenolate
It may increase corticosteroid levels and its adverse effects,
Reference
-Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: A case series. World J Transplant. 2017;7(3):213-221
-Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021;25(1):67-76.
-Medscape drug interactions
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB. This is not a good enough reference in a scientific write-up: Medscape interaction checker
Drug interactions between Rifampicin and INH against immunosuppressants medication
Rifampicin against (TAC, CyA, Sirulimus, and prednisolone;
Rifampcicn is a potent Cyt 450 inducer so enhances the metabolism of the above medications.
Drug level should be monitored closely and the dose should be increased 2-5 fold to avoid graft rejection.
2. Rifampicin against Azathioprine and Mycophenolate;
No drug interaction.
3. INH against TAC/CyA/SIR;
No drug interaction.
4. INH against AZA/MYC;
No drug interaction.
References
[1] Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
[2] Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
[3] Gervasini G, Benítez J, Carrillo JA. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. European Journal of Clinical Pharmacology. 2010;66:755-774. DOI: 10.1007/s00228-010-0857-7
[4] Shah RR, Shah DR. Personalized medicine: Is it a pharmacogenetic mirage? British Journal of Clinical Pharmacology. 2012;74:698-721. DOI: 10.1111/j.1365-2125.2012.04328.x
[5] Sim SC, Kacevska M, Ingelman-Sundberg M. Pharmacogenomics of drug-metabolizing enzymes: A recent update on clinical implications and endogenous e
Rifampicin and immunosuppressive medications interaction As cyclosporine, tacrolimus, sirolimus, MMF, and prednisone are all effective enzyme inducers, rifampicin can significantly reduce their levels or effects by inducing the cytochrome P450 CYP3A and, to a lesser extent, CYP2C enzymes. Rifampicin induces CYP3A4 over a number of days, peaking one week after the drug is started. Following the usage of rifampin, it is advised to 3-5 fold increase the dose of CNI or rapamycin while closely monitoring the serum level. No significant interactions exist between rifampicin and azathioprine.
Isoniazid and immunosuppressive medications interaction Prednisolone may lower plasma concentrations of INH by an unidentified mechanism. In a trial involving 26 TB patients who were administered INH at a dose of 10 mg/kg/day, the administration of a single dose of 20 mg of prednisolone resulted in a 23% drop in plasma INH concentrations and a 38% reduction in plasma drug concentrations. Yet, it is unclear how this connection may manifest clinically. Tacrolimus, but not INH or CNI, can reduce the effects of cyclosporine. There is no obvious interaction between sirolimus, MMF, or azathioprine.
Main challenge with Rifampicin that induce Cyto P 450 and decrease therapeutic level of CNI and mTOR
CNI and mTor
Rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin (Tacrolimus, Cyclospirin) and mTOR inhibitor (Sirolimus) should be increased between three- and five-fold.
Cyclosporin: Clinical practice guidelines from the American Society of Transplantation Infectious Diseases Community of Practice recommend avoiding coadministration of rifampin and cyclosporine if possible; if concomitant use is required a cyclosporine dose increase of 2-fold is recommended.
Ref: 18. Sparkes T, Lemonovich TL, AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants- guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e:13510. [PubMed 30817021]
Prednisolone:
CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic)
Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid.
MMF:
RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
Azathioprine: No interaction
Reference:
Uptodate lexicomp drug interaction between Rifampicin, Isoniazid, and Pyrazinamide and the above drugs. Analyzed 27 Feb 23
Main challenge with Rifampicin that induce Cyto P 450 and decrease therapeutic level of CNI and mTOR CNI and mTor
Rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin (Tacrolimus, Cyclospirin) and mTOR inhibitor (Sirolimus) should be increased between three- and five-fold. Cyclosporin:
Clinical practice guidelines from the American Society of Transplantation Infectious Diseases Community of Practice recommend avoiding coadministration of rifampin and cyclosporine if possible; if concomitant use is required a cyclosporine dose increase of 2-fold is recommended. (2)
Prednisolone:
CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic)
Corticosteroids (Systemic) may decrease the serum concentration of Isoniazid.
MMF:
RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased. Azathioprine: No interaction
Reference:
1- Uptodate lexicomp drug interaction between Rifampicin, Isoniazid, and Pyrazinamide and the above drugs. Analyzed 27 Feb 23
2- Sparkes T, Lemonovich TL, AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants- guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e:13510.
Rifampin will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. INH: will increase the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
Cyclosporine
Rifampin: will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. INH: no significant interaction.
Sirolimus
Rifampin: will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. INH: will increase the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
Azathioprine
INH: no significant interaction. Rifampin: no significant interaction.
Mycophenolate Mofetil
Rifampin: no significant interaction. INH: no significant interaction. Prednisone.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications? Rifampicin :
Rifampicin is a potent inducer of cytochrome P450, so it reduces the drug levels of:
Tacrolimus,
Cyclosporine,
Rapamycin (sirolimus),
Everolimus,
Corticosteroids ( but there is less information about corticosteroids )
. There is high risk of graft rejection with these reductions in drug levels the dose must be adjusted .
Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by UGTs and reduces enterohepatic recirculation and absorption of mycophenolic acid. Also one metabolite of MMF, acyl-glucuronide, gets accumulated and attains higher blood level in presence of rifampicin, which may increase the toxicity or adverse effects.
Rifampicin and azathioprine : No interactions were found
Isoniazid :
Plasma concentrations of isoniazid may be reduced during coadministration with corticosteroids. The mechanism of interaction has not been established, but may involve enhanced hepatic and/or renal elimination of isoniazid .
In a study of 26 patients with tuberculosis given isoniazid 10 mg/kg/day, investigators reported a 23% reduction in plasma isoniazid concentrations for slow acetylators and a 38% reduction for rapid acetylators following the administration of a single 20 mg dose of prednisolone..
No interaction with other immunosuppressants( CNI ,mTORi, MMF ) is found .
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
The interaction of the anti-tuberculous drugs (Rifampicin and INH) Rifampicin: is considered drug inducer. Tacrolimus: lead to decrease the tacrolimus level as it is considered inducer of CYP3A4. Cyclosporine:Rifampin, a potent enzyme inducer, has been demonstrated to increase cyclosporine clearance. Sirolimus:Rifampicin increases the clearance of sirolimus approximately 5.5fold and decreases the maximum concentration (C max ) by 71% Azathioprine: No significant interaction and might decrease Azathioprine clearance. Mycophenolate Mofetil:long-term rifampin therapy causes a marked reduction in dose-corrected MPA exposure when administered simultaneously with MMF. Prednisone:rifampicin increased the plasma clearance of prednisolone by 45%. INH: Tacrolimus:The serum concentration of Tacrolimus can be increased when it is combined with Isoniazid. Cyclosporine:The metabolism of Cyclosporine can be decreased when combined with Isoniazid. Sirolimus: metabolism of Sirolimus can be decreased when combined with Isoniazid. Azathioprine: rifampicin increased the plasma clearance of prednisolone by 45%. Mycophenolate Mofetil:No significant interaction. Prednisone: serum concentration of Isoniazid can be decreased when it is combined with Prednisone. References: The Renal Drug Handbook The Ultimate Prescribing Guide for Renal Practitioners.
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Rifampicin, a strong inducer of cytochrome P450 enzyme (CYP3A4, CYP2C19)
Cyclosporine – it may decrease serum concentration of cyclosporine.
Tacrolimus – it may decrease serum concentration tacrolimus.
Sirolimus – it may decrease serum concentration sirolimus.
Azathioprine – No known interaction
Mycophenolate mofetil – Rifampin may decrease the serum concentration of active metabolites of mycophenolate. Specifically, concentration of mycophenolic acid may be decreased.
Prednisone – it may decrease serum concentration prednisone.
Isoniazid – a minor substrate of CYP2E. It moderately inhibits CYP2E1 and may also induce it, while it weakly inhibits CYP3A4.
Cyclosporine – may increase concentration of cyclosporine.
Tacrolimus – may increase concentration of tacrolimus.
sirolimus – may increase concentration of sirolimus.
Azathioprine – May increase the risk of drug induced liver injury.
No significant interaction with mycophenolate mofetil and prednisolone.
Rifampicin: Drug information. Up to Date [database on the Internet]. Waltham (MA): UpToDate; 2020[cited 27 Feb 2023] Available from: http://www.uptodate.com.
Isoniazid: Drug information. Up to Date [database on the Internet]. Waltham (MA): UpToDate; 2020[cited 27 Feb 2023] Available from: http://www.uptodate.com.
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Rifampicin, being a hepatic enzyme inducer, its interaction with Tacrolimus leads to sub therapeutic Tac. level and potential allograft rejection. Similarly it reduces cyclosporine and Sirolimus blood level. Rifampicin is increasing metabolism of Azathioprine as well. When given simultaneously, Rifampicin reduced the dose-corrected mycophenolate acid exposure, leading to subtherapeutic drug level. Prednisolone concentration is reduced by 45% owing to increased metabolism. INH:
Conversely, as an enzyme inhibitor, it increase the level of CNi bioavailability, however no change in metabolism of cyclosporin was reported. INH might increase levelof Sirolimus for the same reason , however , no reports were found to discuss this happening. Azathioprim administration concumitently with INH might be resultant in Hepatitis and pancytopenia. There is no reported interaction with Mycophenolate Mofitel.
INH might increase level and effect of steroid by reducing its metabolism.on the hand steroid may decrease effect of INH by unknown mechanism.
Reference:
1]Dirk R J Kuypers et al. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase.Clin Pharmacol Ther 2005 Jul;78(1):81-8.2] Mously, Alaa et al.Rifampin Drug Interactions with Tacrolimus in Solid Organ Transplant.Transplantation 102():p S602-S603, July 2018.3] K Sud et al. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipientsMethods Find Exp Clin Pharmacol 2000 Oct;22(8):647-9.
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Both rifampicin (strong) and INH (weak) are enzyme inducers of cytochrome P450 CYP3A4 and will result in a reduction in the serum level of the following drugs
Tacrolimus
cyclosporin
everolimus
Hence in kidney transplant patients, it is adviceable to increase the dose of CNIs and mTORs by 3-5 fold of the baseline to avold graft rejection because of low level of the immunosuppressives
Rifampicin affect the matabolization of glucocorticoid, and the recommendation is to double the dose of the steroid to avoid rejection
Antimetabolites, especially azathioprine are know to cause bone marrow suppression and this could be very severe with concomitant use of alopurinol. The bone marrow suppression of antimetabolites will be severe when used together with INH or rifampicin and as a result, azathioprine is usually advised to be withdrawn when the white cell count is less than 3000/mm3 or 50% drop
Azathioprine also cause elevated liver enzymes (ALT, AST )and this could amplify the hepatotoxicity effect of INH (elevated AST, ALT & bilirubinemia) when used together in treatment of PTB
References
Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, C, et al. Mycobacteria Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022; 11: 1041
Rifampicin is a potent enzyme inducers that can induce cytochrome P450 CYP3A enzyme and to a lesser extent CYP2C so it significantly decrease the level or effect of cyclosporine, tacrolimus, sirolimus,MMF and Prednisone. Induction of CYP3A4 with rifampicin takes several days to occur and peak at 1 week after initiating the drug. Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 3-5 folds, with close follow up of serum level (1)
No significant interaction with azathioprine
INH
Prednisolone may decrease the plasma concentration of INH by unknown mechanism. In a study evaluating 26 TB patients given INH in a dose of 10 mg/kg/day, a 23% reduction in plasma INH concentrations (in slow acetylators) and 38% reduction in plasma drug concentrations (in rapid acetylators) was reported after admisntration of single dose of 20 mg of prednisolone. But the clinical impact of this interaction is not clear
Using INH and CNI may decrease the effects of cyclosporine but not tacrolimus
No significant interaction with azathioprine, MMF or sirolimus
References
1. Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
Severe and sometimes fatal hepatitis associated with isoniazid therapy has been reported and may occur or may develop even after many months of treatment. The risk of developing hepatitis is age related.
The serum concentration of Tacrolimus can be increased when it is combined with Isoniazid.
The metabolism of Mycophenolate mofetil can be decreased when combined with Isoniazid.
Isoniazid may decrease the excretion rate of Mycophenolic acid which could result in a higher serum level.
The serum concentration of Isoniazid can be decreased when it is combined with Prednisone.
The metabolism of Azathioprine can be decreased when combined with Isoniazid.
The metabolism of Sirolimus can be decreased when combined with Isoniazid.
The metabolism of Temsirolimus can be decreased when combined with Isoniazid.
The metabolism of Cyclosporine can be decreased when combined with Isoniazid
=================================================================== Isoniazid- and rifampicin-induced thrombocytopenia
The main mechanisms of thrombocytopenia are decreased production or increased destruction.
Moreover, dilutional and distributional mechanisms may contribute. Before diagnosing thrombocytopenia,
Baysarowich J, Koteva K, Hughes DW, Ejim L, Griffiths E, Zhang K, Junop M, Wright GD: Rifamycin antibiotic resistance by ADP-ribosylation: Structure and diversity of Arr. Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4886-91. doi: 10.1073/pnas.0711939105. Epub 2008 Mar 18
From Wikipedia, the free encyclopedia
Naylor H, Robichaud J. Decreased tacrolimus levels after administration of rifampin to a patient with renal transplant. Can J Hosp Pharm. 2013;66(6):388-392. doi:10.4212/cjhp.v66i6.1313
Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol. 2008;24(3):396-400. doi:10.4103/0970-1591.42625
Sandoz and FDA can help report adverse reactions.www.fda.gov/medwatch
Drug Interactions;
–Rifamycins;
-Have an induction effect on different drug metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
-A lower blood level of these drugs is associated with higher risk of graft rejection.
-Therefore, close monitoring and continuous dose adjustment are highly recommended.
–Rifampin has the most potent enzyme induction effect.
-2-5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
-Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
-Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
-Despite these drug interactions, rifampicin is not contraindicated in SOT recipients.
–Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
-It has been demonstrated to be as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.
-Its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment. -Isoniazid (INH); -Has a potential effect to cause hepatotoxicity and cytopenia, so; it can interact with Azathioprine or MMF to augment their side effects. –Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin and this risk is further accentuated in patients with pre-existing liver disease and alcoholics.
-Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine. -References;
-Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis. 2005;40: 581–587.
-Singh N, Paterson DL. Mycobacterium tuberculosis infection in solidorgan transplant recipients: impact and implications for management. Clin Infect Dis. 1998;27:1266–1277.
-Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet. 2003;42:819–50.
-Sun HY, Munoz P, Torre-Cisneros J, et al. Tuberculosis in solid-organ transplant recipients: disease characteristics and outcomes in the current era. Prog Transplant. 2014;24:37–43.
-Crabol Y, Catherinot E, Veziris N, et al. Rifabutin: where do we stand in 2016? J Antimicrob Chemother. 2016;71:1759–71.
-Hickey MD, Quan DJ, Chin-Hong PV, et al. Use of rifabutin for the treatment of a latent tuberculosis infection in a patient after solid organ transplantation. Liver Transpl. 2013;19:457–61.
–Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
The recommended course of action is to raise the dosage of calcineurin inhibitor or rapamycin by a factor of three to five, while closely monitoring the amounts of the drug in the blood. Rifampin induction of CYP3A4 takes several days to take effect, often reaches its peak within a week, and continues for a few days to several weeks.
Rifabutin has comparable action against M. tuberculosis but poorer cytochrome p450 induction.
Combining isoniazid, rifampin, and pyrazinamide increases hepatotoxicity, especially in liver recipients. Watch the liver function testing. Isoniazid may cause neurotoxicity and peripheral neuropathy.
Aguado, J. M., Torre-Cisneros, J., Fortún, J., Benito, N., Meije, Y., Doblas, A., … & Snydman, D. R. (2009). Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clinical infectious diseases, 48(9), 1276-1284.
The pharmacokinetics of tacrolimus vary greatly between & among individuals.
Tacrolimus has a narrow therapeutic range & its interactions with other drugs, mediated by both P-glycoprotein & CYP3A enzymes, are potentially very important.
Interactions leading to subtherapeutic blood concentrations of tacrolimus increase the likelihood of transplanted organ rejection, whereas interactions resulting in overexposure to tacrolimus are linked to significant toxicity.
Tacrolimus is pumped back into the intestinal lumen by the efflux transporter P-glycoprotein, which essentially determines how much of it is bioavailable.
Tacrolimus blood concentration may rise or fall as a result of P-glycoprotin inhibition or induction, respectively.
Tacrolimus absorption & bioavailability may increase as a result of certain medicines, which are P-glycoprotein substrates, taking up active positions in this pump.
Examples of P-glycoprotein inducers:
Rifampicin
Everolimus & sirolimus
Phenytoin & carbamaepine
Dabigatran
Examples of P-glycoprotein inhibitors:
Macrolides
Cyclosporine
Verapamil & diltiazem
Captopril
Carvedilol
Ketoconazole
Examples of P-glycoprotein substrates:
Azithromycin
Cortisol & dexamethasone
Digoxin
Colchicines
Drugs that interact with tacrolimus through CYP3A enzymes Inhibitors include:
Macrolides
fl uconazole & ketoconazole
verapamil
methylprednisolone
metoclopramide
Substrates:
Amlodipine
Atorvastatin
Warfarin
Nifedipine
Inducers:
Aluminium hydroxide
Dexamethasone
Isoniazid
Carbamazepine
Rifampicin
Sirolimus
Phenytoin
Reference
A Nemanja K. Rančić, Neven N. Vavić, Aleksandra M. Kovačević, Momir M. Mikov, Viktorija M. Dragojević – Simić,Drug-drug interactions of tacrolimus, Hospital Pharmacology. 2015; 2(3):291-296 UDC: 615.37.015.4 ==========================
·Cyclosporine
CsA is a lipophilic molecule that is poorly absorbed when given orally.
Absorption occurs within 30 minutes, & peak serum concentration (Cmax) is seen 2 to 4 hours after the dose. There is wide variations in inter- & intrapatient bioavailability, ranging from 1% & 89%.
There are numerous medication interactions found. Where possible, co-administration of interaction medications should be avoided; nevertheless, if it is unavoidable, thorough therapeutic monitoring & dosage modification are required to prevent therapeutic failure or toxicity.
Interaction may result from pharmacokinetic, physiologic, or pharmacologic alterations. The gut, lipoproteins, liver, & kidneys are possible sites of contact.
Drugs that increase cyclosporine plasma concentrations include:
References
Rapamune® (sirolimus) Oral Solution and Tablets NDA 21-083/S-030 NDA 21-110/S-038 Page 3 ==========================
·Azathioprine Use with xanthine oxidase (XO) inhibitors (allopurinol, febuxostat):
XO pathway normally inactivate azathioprine.
Inhibition of this enzyme will lead to increased plasma concentrations of azathioprine & its metabolites, 6-MP, leading to toxicity.
Patients receiving azathioprine & allopurinol concomitantly should have a dose reduction of azathioprine, to 1/ 3 to 1/ 4 the usual dose.
Concomitant use of azathioprine with febuxostat is not recommended.
Further dose reduction or alternative therapies considered for patients with low or absent TPMT activity receiving azathioprine & xanthine oxidase inhibitors because both TPMT & XO inactivation pathways are affected.
Use with Aminosalicylates(sulphasalazine, mesalazine, or olsalazine):
Aminosalicylate derivatives inhibit the TPMT enzyme. Concomitant use of these agents with azathioprine should be done with caution.
Use with Other Agents Affecting Myelopoesis (e.g., co-trimoxazole):
May lead to exaggerated leukopenia, especially in KTX recipients.
Use with ACE inhibitors:
This can induce anemia & severe leukopenia.
Use with Warfarin:
Azathioprine may inhibit the anticoagulant effect of warfarin.
Use with ribavirin:
Can induce severe pancytopenia & may increase the risk of azathioprine-related myelotoxicity.
IMDH is required for one of the metabolic pathways of azathioprine. Ribavirin inhibits IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-MTITP, which is associated with myelotoxicity (neutropenia, thrombocytopenia, & anemia).
CBC should be checked on patients using azathioprine with ribavirin every week for the 1st month, twice monthly for the 2nd & 3rd months of treatment, & then monthly.
References
IMURAN ® (azathioprine) 50-mg Scored Tablets PRODUCT INFORMATION ==========================
·Mycophenolate Mofetil Use with anti-bacterial agents Metronidazole:
Though, I don’t think it would be necessary to do so, except if there is a compelling indication for the use of this antibiotic (guided by sensitivity results) for a prolonged duration.
Due to strong interactions between this type of medication and the calcineurin inhibitors and rapamycin, rifampin should be used with caution (sirolimus). Tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus serum concentrations are decreased by the rifamycins (particularly rifampin) through stimulation of the cytochrome p450 isoenzyme CYP3A4, and taking a rifamycin together with these medications has been linked to the emergence of rejection.
Rifamycins also reduce levels of glucocorticoids, although this has been less well characterized If rifampin is used Increase dose of calcineurin inhibitor or rapamycin, monitor serum concentrations. Streptomycin is generally avoided in SOT recipients due to risk of nephrotoxicity Azathioprine and Mycophenolate Mofetil – No interactions found
Rifampicin:
Rifampicin will decrease level and affect of tacrolimus/ Prednisolone/ Sirolimus by affecting hepatic and intestinal enzymes cyp3A4; (So need to be avoided rifampicin with these drugs or use alternative therapy.
Cyclosporine need modification of dose because Rifampicin will decrease level and affect by affecting hepatic and intestinal enzymes cyp3A4.
No dose adjustment of MMF and azathioprine with rifampicin.
Isoniazid:
Prednisone decrease effect of INH by unknown mechanism.
Isoniazid will decrease level and affect of Sirolimus by affecting hepatic and intestinal enzymes cyp3A4; So should be avoided or use alternative therapy.
Isoniazid with tacrolimus should be use with caution and monitoring because Isoniazid will decrease level and affect of tacrolimus.
No dose adjustment with cyclosporine and azathioprine or MMF.
Tacrolimus – rifampin will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. isoniazid will increase the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
Cyclosporine – rifampin will decrease the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. rifampin will decrease the level or effect of cyclosporine by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely.
Sirolimus – rifampin will decrease the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Rifampin will decrease the level or effect of sirolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Isoniazid will increase the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
Azathioprine – No interactions found
Mycophenolate Mofetil – No interactions found
Prednisone – Rifampin will decrease the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Rifampin will decrease the level or effect of prednisone by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Isoniazid will increase the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
The rifamycins, particularly rifampin, reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4.
The combination of rifampin with members of this class of drugs can lead to the development of rejection unless dose adjustments and therapeutic drug monitoring are performed carefully.
Rifabutin is an attractive alternative to rifampin because it is a weaker inducer of cytochrome p450. However, there is less experience with rifabutin in the treatment of TB.
Similarly, the long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout. Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by the simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.
References:
· Tuberculosis in solid organ transplant candidates and recipients – UpToDate · Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther. 2005 Jul;78(1):81-8. doi: 10.1016/j.clpt.2005.03.004. PMID: 16003296.
1- rifampicin RFM is a strong cytochrome (CY) P3A4 inducer. 2- it significantly reduce blood levels of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi), steroids and even mycophenolate mofetil (MMF) by inducing CYP3A4-mediated immunosuppressant metabolism.
3- to minimize the effect of this drug-to-drug interaction without compromising efficacy against TB, one recommendation is to use rifabutinRFB instead of RFM. RFB is structurally similar to RFM, has the same potency against TB and has almost the same mechanism of interaction with immunosuppressants. Although, in contrast to RFM, RFB is a weak CYP3A4 inducer and therefore, may not significantly reduce immunosuppressant trough levels.
Yu-Chen Wang , Noruel Gerard Salvador, Chih-Che Lin , Chao-Chien Wu , Ting-Lung Lin , Wei-Feng Lee , Yi-Chia Chan , Chao-Long Chen , Jeffrey Samuel Co , Domelle Dave Encarnacion. Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. Biomedical Journal. Volume 44, Issue 6, Supplement 2, December 2021, Pages S162-S170
Rifampicin is a potent enzyme inducer. Therefore, its use is associated with a severe drops in the serum levels of Cyclosporine, Tacrolimus, everolimus and Sirolimus due to the induction of the CYP3A enzyme (1).
Isoniazid (INH) has a potential effect to cause hepatotoxicity and cytopenia, so, theoretically, it can interact with Azathioprine or MMF to augment their side effects, as illustrated in the attached table (2).
I could not find a direct interaction between prednisone and Rifampicin or Isoniazid (INH).
2) Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
Tacrolimus
rifampicin decrease the plasma levels
INH will increase the levels
Cyclosporine
rifampicin decrease the plasma levels
Sirolimus
rifampicin decrease the plasma levels
INH will increase the plasma levels
Azathioprine
No interaction
Mycophenolate Mofetil
Mycophenolate is metabolized into mycophenolic acid, which undergoes glucuronidation by uridine diphosphate glucuronosyltransferases in the liver, kidney, and intestine to its inactive metabolite (7-O-glucuronide). Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by UGTs and reduces enterohepatic recirculation and absorption of mycophenolic acid. Also one metabolite of MMF, acyl-glucuronide, gets accumulated and attains higher blood level in presence of rifampicin, which may increase the toxicity or adverse effects. Hence in presence of rifampicin, its plasma level should be monitored, and the dose should be adjusted accordingly
Prednisone
Rifampicin is a potent liver enzyme inducer, which increases the metabolism of the steroids, thereby reducing the effect of steroids by blood levels. Steroid dose should be increased initially, and should be gradually decreased, once rifampicin is discontinued.
Anti-TB medications and their adverse effects
First line anti MTB includes, rifampicin, INH, pyrazinamide, ethambutol
The average concerns regarding medications, including anti-MBT pharmaceuticals, are efficacy, safety, drug-drug interactions, adverse effects, toxicity, and cost.
Utilization of anti-TB drugs after SOT Concern exists regarding drug interactions with other immunosuppressive medications, specifically CNI (Tacrolimus, cyclosporine), mTOR inhibitors such as sirolimus and everolimus, antimetabolites (azathioprine and MMF), and steroids.
RIFAMPICIN
Rifampicin is considered the first-line anti-tuberculosis drug due to its high bactericidal activity against mycobacteria. It inhibits protein synthesis by inhibiting mRNA transcription and synthesis, and it is metabolized by the liver. Rifampicin acts as an enzyme inducer via cytochrome 450, CYP3A4, and induces certain drug transporter proteins, including intestinal and hepatic P-glycoprotein. and can reduce the level of CNI, sirolimus, and everolimus to undetectable levels, so we need to increase the dose of tacrolimus or Cyclosporine by 3-5 folds (sometimes will give TID dose) with close monitoring by trough level, also need frequent LFT monitoring for transaminitis weekly in the first two months then every month, rifabutin as an alternative can be used, and it’s more well-tolerated than rifam Dose: rifampicin 600 mg/d; rifabutin 300 mg/d.
Sirolimus follows the same protocol as CNI and requires frequent dose adjustments and monitoring.
No interaction between azathioprine, MMF, and rifampin resulted in a decrease in MMF concentration due to enterohepatic circulation.
INH
Isoniazid and rifamycin can cause drug-induced hepatitis, and rifampicin and pyrazinamide can cause severe liver toxicity (3). Therefore, close monitoring is required twice per week for the first two weeks, then once per week for the first two months; if liver enzymes increase fivefold from baseline, discontinuation should be considered.
INH and hormones
Prednisolone significantly decreased the plasma concentrations of isoniazid in both slow and rapid inactivators (2).due to increased renal clearance of isoniazid in both slow and rapid inactivators and an increased rate of acetylation of isoniazid in slow inactivators, but concomitant administration of rifampin significantly modified the effect of prednisolone on isoniazid disposition.
MMF combined with azathioprine, sirolimus, and CNI
Reference:
Sorohan, B. M., Ismail, G., Tacu, D., Obrișcă, B., Ciolan, G., Gîngu, C., Sinescu, I., & Baston, C. (2022). Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. In Pathogens (Vol. 11, Issue 9). https://doi.org/10.3390/pathogens11091041
interaction of the anti-tuberculous drugs (Rifampicin and INH)
https://journals.lww.com/transplantjournal/Abstract/2018/07001/Rifampin_Drug_Interactions_with_Tacrolimus_in.963.aspx#:~:text=Drug%E2%80%93%20drug%20interaction%20between%20tacrolimus%20and%20the%20cornerstone,may%20lead%20to%20increase%20the%20risk%20of%20rejection.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin: first-line anti-TB drug
· Rifampicin is an enzyme inducer of CYP34A(Rifabutin is a less potent cytochrome inducer), thus increasing the metabolism of CNIs (Tacrolimus, cyclosporine) and MTORs (Sirolimus and Everolimus). Moreover, it reduces the levels of prednisone (increases clearance by around 45% and reduce the amount of drug available to the tissues by around 66%) and MMF due to interaction with entero-hepatic circulation.. However, it has no effect on Azathioprine.
· Accordingly, we need to increase the dose of CNIs(3-5 times), Sirolimus if used and possibly steroids and MMF. Close monitoring of immunosuppression and checking trough levels of CNIs is required with the initiation and after the discontinuation of rifampicin or rifabutin.
Isoniazid: first-line anti-TB drug
· INH increases the metabolism and renal clearance of prednisolone. So, decreases INH effectiveness. INH has no effects on anti-metabolites(MMF and azathioprine) CNIs and sirolimus.
We have to be aware that both Rifampicin and INH are hepato-toxic. Thus close monitoring of liver functions is required twice weekly in the first two weeks then weekly in the first two months and discontinue treatment if liver enzymes increases by 5 folds from baseline.
References:
1. Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother. 1980 Nov;18(5):661-6.
2. Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76.
● Rifampicin decrease the levels of CNi , mTORi and affects steroid metabolization,
and even mycophenolate mofetil (MMF) by inducing CYP3A4-mediated immunosuppressant metabolism
which increases the risk of rejection
☆ Therefore calcineurin and mTOR inhibitors levels should be monitored and increased three- and five-fold and the glucocorticoid dose should be doubled
☆ An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 or fluoroquinolones
● Concomitant administration of INH and CyA is safe and is not associated with any appreciable alterations in the bioavailability of CyA neither MMF, TAC, AZA, m-TOR .
References :
1) . Phyo Wai Lwin,Yi Yi Htun, Aung Kyaw Myint, and Htar Kyi Swe . Posttransplantation tuberculosis management in terms of immunosuppressant cost: a case report in Myanmar .Korean J Transplant. 2021 Mar 31; 35(1): 48–52.
2) . K Sud et al.Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients .Methods Clin Pharmacol. 2000 Oct.
Rifampicin effects on Immunosuppression-
Rifampicin decreases the level of Tacrolimus,cyclosporine and sirolimus.It also decreases the bioavailablity of Mycophenolate and prednisolone. No interaction between azathioprine and rifampicin.
INH effects on immunosuppression-
No interaction found except with Cyclosporine where it may decrease the level the cyclosporine but many reported no effect on bioavailablity.
Anti TB drugs and
1-Rifambin :
May cause decrease in taclolimus,cyclosporine and sirolimos level ,
Increase in mycophinolate level,no interaction with azathioprine.
2_INH:
Cause no interaction with tacrolimus, cyclosporine,MMF , Azathioprine.
Predlone may decrease INH level.
Anti-TB drugs are: rifampicin, INH, pyrazinamide, ethambutol. There are concerns about their effects on the metabolism of immunosuppressive drugs such as tacrolimus, sirolimus, MMF or AZA and prednisolone.
Rifampicin is an anti-TB with potent and bactericidal effect by blocking mRNA synthesis which is metabolized by liver.
It induces cytochrome P450, CYP3A4, and some drug transporters like p-glycoproteins.
So it reduces blood levels of tacrolimus and cyclosporine, sirolimus.
The dose of these drugs especially CNIs should be increase to 3 to 5 folds to have the same drug levels and close drug level and LFT monitoring are needed.
Sirolimus needs higher doses and close monitoring too. Rifampicin reduces MMF level by interaction with enterohepatic circulation but has no effect on azathioprine level.
INH is hepatotoxic especially in combination with rifampicin and LFT monitoring twice weekly and then weekly is preformed and in case of 5-fold increase, discontinuing is considered. Prednisolone causes significant decrease in isoniazid concentration by increasing the rate of acylation of INH.
MMF and azathioprine and CNI have no effect on INH level.
Reference:
Sorohan, B. M., Ismail, G., Tacu, D., Obrișcă, B., Ciolan, G., Gîngu, C., Sinescu, I., & Baston, C. (2022). Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. In Pathogens (Vol. 11, Issue 9). https://doi.org/10.3390/pathogens11091041
The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein.
– Rifampicin: decrease tacrolimus exposure
– INH: no effect
– Rifampicin: Decreased cyclosporine exposure
– INH: no effect
– Rifampicin: Decreased sirolimus exposure
– INH: no effect
– Rifampicin:
– INH:
– Rifampicin: Decreased MPA exposure
– INH: no coments
– Rifampicin: Decreased methylprednisolone, prednisone, prednisolone exposure
– INH: Decreased INH exposure
REFERENCE:
– KDIGO clinical practice guideline for the care of kidney transplant recipients: A Summary [Internet]. [cited2023Mar5]. Available from: https://kdigo.org/wp-content/uploads/2017/02/KITxpGL_summary.pdf
– Wang YC, Salvador NG, Lin CC, Wu CC, Lin TL, Lee WF, Chan YC, Chen CL, Co JS, Encarnacion DD. Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. Biomed J. 2021 Dec;44(6 Suppl 2):S162-S170. doi: 10.1016/j.bj.2020.08.010. Epub 2020 Sep 4. PMID: 35300949; PMCID: PMC9068555.
Rifampicin, a potent inducer of cytochrome p450 3A4 and p-glycoprotein, interferes with immunosuppression metabolism and decrease the level of CNI (cyclosporin, tacrolimus), Therefore it is suggested to closely monitoring of CNI or mTORi levels while using Rifampicin. mTOR inhibitors (sirolimus, everolimus) are affecting glucocorticoid metabolism. therefore CNI and mTOR inhibitors dose should be increased between three and five-fold
Rifampicin increases MPA metabolism by induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases,
Rifampicin increases the metabolism of cortisol, increasing clearance by 45%, thereby lowering prednisolone AUC by 66% and reducing its half-life by 40-60%. higher steroid doses may be required during co-administration with rifampicin in order to counter these effects
INH have no significant drug interaction with the given medication
Rifampicin, a potent inducer of cytochrome p450 3A4 and p-glycoprotein, interferes with immunosuppression metabolism and decrease the level of CNI (cyclosporin, tacrolimus), mTOR inhibitors (sirolimus, everolimus) and affects glucocorticoid metabolism. So dose of CNI and mTOR inhibitors should be increased between three and five-fold and the glucocorticoid dose should be doubled during treatment.
INH have no significant drug interaction with the given medication.
1. Calcineurin inhibitors (Tacrolimus, Cyclosporine) and mTORi Sirolimus
· Rifampicin being a potent inducer of cytochrome P450 enzymes (CYP3A4 & CYP3A5) as well as P. glycoprotein in the liver – leads to increased metabolism of CNI (tacrolimus, cyclosporine) and mTORi (Sirolimus), thereby decreases the plasma levels of CNI and Sirolimus to subtherapeutic levels, thus increases risk of allograft rejection.
– ATT induced hepatitis on the other hand, can have bizarre effect on drug metabolism, can increase the level of CNI causing nephrotoxicity.
– KDIGO guidelines suggests close monitoring of CNI or mTORi levels while using Rifampicin.
2. Azathioprine
3. Mycophenolate Mofetil
– It could potentially lead to MPA underexposure and loss of clinical efficacy, may need dose adjustment of mycophenolate.
4. Prednisone
· Rifampicin increases the metabolism of cortisol, increasing clearance by 45%, thereby lowering prednisolone AUC by 66% and reducing its half-life by 40-60%. higher steroid doses may be required during co-administration with rifampicin in order to counter these effects.
· Isoniazid increases serum prednisone levels by inhibition of CYP3A4 induction.
References:
1. Bhagat V, Pandit RA, Ambapurkar S, et al. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021; 25(1): 67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
2. British National Formulary [Internet]. NICE. [cited 2023Mar5]. Available from: https://bnf.nice.org.uk/ 
3. KDIGO clinical practice guideline for the care of kidney transplant recipients: A Summary [Internet]. [cited2023Mar5]. Available from: https://kdigo.org/wp-content/uploads/2017/02/KITxpGL_summary.pdf
4. Naylor H, Robichaud J. Decreased tacrolimus levels after administration of rifampin to a patient with renal transplant. Can J Hosp Pharm. 2013 Nov;66(6):388-92. Available from: https://pubmed.ncbi.nlm.nih.gov/24357873/
5. Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clinical pharmacology and therapeutics. 2005 Jul;78(1):81-8. PubMed PMID: 16003296. Epub 2005/07/09.
6. Matre V ET, Satyanarayana G, Page RL, et al. Pharmacokinetic Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids. Ann Transplant. 2018 Jan 23; 23: 66-74. doi: 10.12659/aot.906164. PMID: 29358572; PMCID: PMC6248062.
1) Interaction between Rifampicin (CYP3A4 Inducer) and:
· Tacrolimus: Rifampicin may decrease the serum concentration of Tacrolimus.
· Cyclosporine: Rifampicin may decrease the serum concentration of Cyclosporine
· Sirolimus: Rifampicin may decrease the serum concentration of Sirolimus
· Azathioprine: no interaction with Rifampicin
· Mycophenolate Mofetil: Rifampicin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
· Prednisone: Rifampicin may decrease the serum concentration of Prednisone.
2) Interaction between INH (CYP3A4 Inhibitor) and:
· Tacrolimus: INH may increase the serum concentration of Tacrolimus
· Cyclosporine: INH may increase the serum concentration of Cyclosporine
· Sirolimus: INH may increase the serum concentration of Sirolimus
· Azathioprine: no interaction with INH
· Mycophenolate Mofetil: no interaction with INH
· Prednisone: may decrease the serum concentration of Isoniazid.
https://www.uptodate.com/drug-interactions/?search=drug%20interactions%20with%20rifampicin&usage_type=panel&source=panel_search_result&display_rank=2#di-document:~:text=Lexicomp%C2%AE%20Drug%20Interactions
Rifampicin :
Reduces level of Tacrolimus- Cyclosporine- sirolimus- MMF- prednisolone
●inducer of CYP 450 3A4-mediated metabolism
●P glycoprotein-mediated efflux of sirolimus by rifampicin
●Interference of enterohepatic circulation of MMF by rifampicin
HOWEVER rifampicin doesn’t interfere with Azathioprine
INH
Using prednisone with INH deceased the level of INH because it increases renal clearance of the INH and inactivation
THere is no interference between INH and Tacrolimus- Cyclosporine- Sirolimus- azathioprine – MMF
Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein. Drugs which are metabolized by these enzymes have interaction with Rifampicin –CNIs (cyclosporine, tacrolimus), mTOR inhibitors levels are decreased with Rifampicin so their dose should be increased 3-5 fold before starting this drug in order to reduce the chances of rejection.
INH inhibit CP450 3A4 inhibitor and monoamine oxidases, therefore, drugs like CNIs , mTOR inhibitors levels will be increased and need dose reduction while using this drug.
Both drugs have effect on steroids and Mycophenolate mofetil. Steroids will decrease the level of INH ,however, Rifampicin will increase the metabolism of prednisolone and its clearance. Rifampicin induces Uridine diphosphate-glucuronosyltransferases which will increase glucuronidation of mycophenolic acid by the liver, thus reducing entero-hepatic recirculation and also absorption of mycophenolic acid leading to their reduce level. However, concomitant use of INH with MMF can cause hepatotoxicity and cytopenias.
In short, drug levels should be monitored frequently to avoid side effects and lessen the chances of rejection.
REFERENCE:
1-Sorohan, B.M.; Ismail, G.; Tacu, D.; et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041.
2-Aguado JM, Torre-Cisneros J, Fortun J. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish society of infectious diseases and clinical microbiology. Clin Infect Dis. 2009;48(9):1276–1284.
Rifampicin and Rifabutin are known to induce the enzymes of CYP3A4….Isoniazid does not induce the metabolism of CYP3A4 and hence no interaction with immunosuppressants are noted with isoniazid
Rifampcin is an enzyme inducer….Decrease the level of calcineurin inhibitors, mTOR inhibitors leading to acute graft rejection…. Tacrolimus , cyclosporine and sirolimus levels are reduced in the serum when patients are on rifampicin….Levels of prednisolone are also reduced while of rifampicin….there is no effect of rifampicin on azathioprine metabolism….. MMF is metabolized into Mycophenolic acid which undergoes glucuronidation by uridine diphosphate glucouronosyl transferase in the liver and kidney to an inactive metabolite…rifampicin induces the enzyme of UGT and decreases the level of MMF active metabolite….
Isoniazid is a CYP3A4 inhibitor but it is a weaker inhibitor as compared to Rifampicin…. Concomitant use of INH with MMF may exert more bone marrow cytopenia
Rifampicin is strong inducer of enzyme CYP3A4. It is associated with increased metabolism of CNIs and mTOR, therefore the levels of these drugs are reduced. The dose of CNI and mTOR needs to be increased 2-5 time with monitoring of trough levels and monitoring for rejection.
The effect of Rifampicin on MMF is less pronounced compared with CNI and MTOR, but is associated with lower MMF levels.
There is no interaction of Rifampicin with AZA.
Rifampicin reduces the effects of steroids so dose should be increased up to 2 times.
Isoniazid is a CYP3A4 enzyme inhibitor, leading to increased levels of CNI and mTOR, the effect on these drugs is not significant.
Concomitant use of INH with MMF/AZA increases bone marrow suppression.
Use of Steroids and Isoniazid together is associated with reduced levels of isoniazid .
Drug interaction;
Rifampicin is a potent enzyme inducer of cytochrome P450 (CYP3A4 inhibitors).
1. Tacrolimus à rifampicin decrease the concentration.
2. Cyclosporine à rifampicin decreases the level.
3. Sirolimus à rifampicin decreases the level.
4. Azathioprine à no interaction seen.
5. Mycophenolate Mofetil à decreases the level.
6. Prednisolone à may decrease the concentration of prednisolone.
7. Isoniazid à may increases the level of sirolimus, cyclosporine, and tacrolimus, although, it decreases the concentration of prednisolone.
No drug interaction seen between the INH and MMP, AZA.
References;
1. https://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus?search=drug%20interaction%20in%20between%20Isoniazid%20and%20cyclosporine%20and%20tacrolimus&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=1.
2. https://www.uptodate.com/contents/kidney-transplantation-in-adults-maintenance-immunosuppressive-therapy?search=drug%20interaction%20in%20between%20rifampcin%20and%20cyclosporine%20and%20tacrolimus&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=2.
Rifampicin is a potent cytochrome P3A4 inducer [CYP3A4]. As such it induces metabolism of calcineurin inhibitors, mammalian target of rapamycin inhibitors, mycophenolate mofetil and steroids. As a result of this action it significantly reduces the blood trough levels of Tacrolimus, cysclosporine. Sirolimis , mycophenolate mofetil and Prednisone.
Isoniazid is an inhibitor of the cytochrome P450 system, and the result of this effect is that it will increase the trough levels of the afor mentioned medications. A study by Sud K et al showed hpwever, that this did nmot happen with their patients
REFERENCES
Yu-Chen Wang et al.Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. biomedicL Journal. Volume 44. Issue 6. December 2021
Sud K, Muthukumar T, Singh B, Garg SK, Kohli HS, Jha V, Gupta KL, Sakhuja V. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients. Methods Find Exp Clin Pharmacol. 2000 Oct;22(8):647-9. doi: 10.1358/mf.2000.22.8.802278. PMID: 11256238
1) Interaction between Rifampicin (CYP3A4 Inducer) and:
· Tacrolimus: Rifampicin may decrease the serum concentration of Tacrolimus.
· Cyclosporine: Rifampicin may decrease the serum concentration of Cyclosporine
· Sirolimus: Rifampicin may decrease the serum concentration of Sirolimus
· Azathioprine: no interaction with Rifampicin
· Mycophenolate Mofetil: Rifampicin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
· Prednisone: Rifampicin may decrease the serum concentration of Prednisone.
2) Interaction between INH (CYP3A4 Inhibitor) and:
· Tacrolimus: INH may increase the serum concentration of Tacrolimus
· Cyclosporine: INH may increase the serum concentration of Cyclosporine
· Sirolimus: INH may increase the serum concentration of Sirolimus
· Azathioprine: no interaction with INH
· Mycophenolate Mofetil: no interaction with INH
· Prednisone: may decrease the serum concentration of Isoniazid.
https://www.uptodate.com/drug-interactions/?search=drug%20interactions%20with%20rifampicin&usage_type=panel&source=panel_search_result&display_rank=2#di-document:~:text=Lexicomp%C2%AE%20Drug%20Interactions
Drug interactions of Anti Tubercular Rifampicin, INH with Immunosuppressant Tacrolimus, Cyclosporine, Sirolimus, Azathioprine, Mycophenolate Mofetil, Prednisone:
· Rifampicin is a potent enzyme inducer of cytochrome P 450, so reduce the levels of CNI (Tacrolimus, Cyclosporine), mTOR inhibitors (Sirolimus) and corticosteroids ( Prednisone ).Thus will lead to low levels of Cyclosporine, Tacrolimus, Sirolimus and Prednisolone.
· Rifampicin does not affect metabolism of antimetabolites (MMF and Azathioprine) but concomitant use may worsen adverse events like cytopenias.
· On the other hand Isoniazid is an inhibitor of cytochrome P450 thus it will increase the levels of CNI (Tacrolimus, Cyclosporine), mTOR inhibitors (Sirolimus) and corticosteroids (Prednisone) though this effect is not significant.
· Isoniazid also cause cytopenias. So, it will worsen cytopenia caused by MMF and azathioprine if given concurrently.
Reference:
Medscape
UpToDate
RFM is a strong cytochrome (CY) P3A4 inducer. RFM can significantly reduce blood levels of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi) through induction of P-glycoprotein mediated efflux transport mediating mTORi metabolism so the dose of CNIs and mTORs should be increased by 3-5 fold,
RFM reduces blood levels of mycophenolate mofetil (MMF) “that is better be reduced or held for 2 months in active TB ” through induction of uridine diphosphate glucuronosyltransferases, which mediate MMF metabolism
RFM affects the metabolization of glucocorticoid, and the dose of the steroid should be increased up to 2 fold
so for the interactions mentioned above, RFB is preferred being a less enzyme inducer
INH, though a weak enzyme inducer, no direct interactions with the immunosuppressants are strongly suggested but it may increase the risk of adverse events caused by other anti-tuberculous drugs
reference
M. Niemi, J.T. Backman, M.F. Fromm, P.J. Neuvonen, K.T. Kivisto Pharmacokinetic interactions with rifampicin clinical relevance Clin Pharmacokinet, 42 (2003), pp. 819-850
in general rifampicin is inducer of cytochrome P450 enzyme in liver which increases metabolism and REDUCES THE DRUG LEVEL IN BLOOD of tacrolimus, cyclosporin , sirolimus , and even steroids
this start within hours of taking rifampicin and peaks at 2 weeks and same time is required to return to baseline
CNI dose need to be increased 3 folds , steroid dose need 2 fold increases with intense serum level monitoring
Level of MMF is also reduced but not so intensely with the use of rifampicin
Refabutin is a better replacement of rifampicin with less effect of immunosuppression drugs
on the contrary isoniazide INH inhibits the cytochrome P450 enzyme and drug level can get ELEVATED leading to more immunosuppression and drug toxicity
INH is a WEAK inhibitor of cytochrome P450
rifampin + tacrolimus
isoniazid + tacrolimus
rifampin + cyclosporine
rifampin + sirolimus
isoniazid + sirolimus
rifampin + prednisone
isoniazid + prednisone
Calcineurin inhibitors (Tacrolimus, Cyclosporine) and Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
References:
Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clinical pharmacology and therapeutics. 2005 Jul;78(1):81-8. PubMed PMID: 16003296. Epub 2005/07/09. eng
Van Matre ET, Satyanarayana G, Page 2nd RL, Levi ME, Lindenfeld J, Mueller SW. Pharmacokinetic Drug-Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids. Ann Transplant. 2018 Jan 23;23:66-74. doi: 10.12659/aot.906164. PMID: 29358572; PMCID: PMC6248062.
DRUG INTERACTIONS;
REF;
1. Rifampicin:
a) Rifampicin and tacrolimus/cyclosporine
Rifampicin is coded by the British National Formulary (BNF) as having a severe interaction with calcineurin inhibitors (CNI) such as tacrolimus and cyclosporine. Tacrolimus is a CYP3A4 inhibitor, whilst rifampicin is a inducer of this enzyme pathway. The danger of the interaction is that, as a potent inducer of the liver cytochrome P450 enzymes (CYP3A4 & CYP3A5), rifampicin leads to increased metabolism of tacrolimus/cyclosporine which may subsequently produce subtherapeutic immunosuppression levels putting the patient at risk of allograft rejection. If the two medications are co-prescribed, close monitoring of CNI levels must be undertaken and an increased CNI dose requirement should be anticipated.
b) Rifampicin and sirolimus
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is also coded by the BNF as having a severe interaction with rifampicin due to cytochrome P450 enzyme induction: increased metabolism of sirolimus potentially results in subtherapeutic immunosuppression levels increasing the risk of allograft rejection.
KDIGO guidelines advise that the same TB prophylaxis or treatment regime can be used for kidney transplant recipients as for the local general population; however, close monitoring of CNI or mTORi levels is imperative and where possible clinicians should consider whether rifampicin could be substituted with rifabutin to reduce the risk of this significant interaction and also the risk of acute kidney injury associated with rifampicin.
c) Rifampicin and azathioprine
No significant interaction
d) Rifampicin and mycophenolate mofetil
Mycophenolate mofetil is also coded by the BNF as having a severe interaction with rifampicin- this is owing to the increased metabolism of mycophenolate which can expose the patient to insufficient immunosuppression and risk allograft rejection (particularly with long term use). However, the interaction is much less pronounced that that between CNI and rifampicin. The need for dose adjustment of mycophenolate should be anticipated.
e) Rifampicin and prednisolone
Rifampicin is coded by the BNF as having a moderate interaction with prednisolone. It is recognised that rifampicin can decrease the effectiveness of prednisolone (increased metabolism through rifampicin being an inducer of liver enzymes resulting in lower plasma levels of prednisolone). Clinicians should be aware that higher steroid doses may be required during co-administration with rifampicin in order to counter these effects.
2. Isoniazid
a) Isoniazid and tacrolimus/cyclosporine
Although co-prescription of Isoniazid and tacrolimus may have some small effect on trough CNI levels, the clinical impact of this is not reported to be significant and therefore the BNF does not list isoniazid as a drug which interacts with tacrolimus or cyclosporine.
b) Isoniazid and sirolimus
No clinically significant interaction is noted between isoniazid and sirolimus.
c) Isoniazid and azathioprine
Isoniazid does not have any clinically significant effect on the metabolism of azathioprine. However, prescribers should be mindful of the recognised side-effects of isoniazid which include hepatotoxicity and agranulocytosis. Bone marrow depression (dose related) is recognised in the BNF as a common side effect of azathioprine, alongside hepatotoxicity and agranulocytosis which occur less frequently. Careful monitoring is advisable during co-prescription of these medications to avoid bone marrow over-suppression and dose adjustment may be required in view of this.
Does Isoniazid have an additive effect on the bone marrow?
The mechanism through which azathioprine and isoniazid cause myelosuppression is not clearly defined. However, the myelotoxic effects of both medications on an individual basis are among the more common medication causes of bone marrow toxicity and therefore the risk/benefit of co-prescribing both medications simultaneously must be very carefully considered and, if indicated, the lowest possible dose should be used in conjunction with careful blood count monitoring.
d) Isoniazid and mycophenolate mofetil
Mycophenolate is not listed in the BNF as having a clinically significant interaction with isoniazid. However, prescribers must be mindful of both isoniazid and mycophenolate’s recognised side-effects on the bone marrow and careful full blood count monitoring is important.
e) Isoniazid and prednisolone
Although it is recognised that prednisolone can reduce the plasma concentration of isoniazid this interaction is not usually clinically significant and as such there is not a significant interaction when considering co-prescription of the two medications.
References:
British National Formulary [Internet]. NICE. [cited 2023Mar5]. Available from: https://bnf.nice.org.uk/
KDIGO clinical practice guideline for the care of kidney transplant recipients: A Summary [Internet]. [cited2023Mar5]. Available from: https://kdigo.org/wp-content/uploads/2017/02/KITxpGL_summary.pdf
Naylor H, Robichaud J. Decreased tacrolimus levels after administration of rifampin to a patient with renal transplant. Can J Hosp Pharm. 2013 Nov;66(6):388-92. Available from: https://pubmed.ncbi.nlm.nih.gov/24357873/
Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Chapter 16 – Hematopoietic System, Editor(s): Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Fundamentals of Toxicologic Pathology (Second Edition), Academic Press, 2010, Pages 491-512. Available from: https://www.sciencedirect.com/science/article/pii/B9780123704696000167
Rifampicin Interactions
Rifampicin is a potent CYP3A4 inducer. Hence it will reduce drug levels of Tacrolimus, Cyclosporine, Sirolimus and MMF. This may lead to rejection. It is important to closely monitor drug levels, which may need to be increased 2-5fold. Where possible, Rifabutin is a better option as it is a weaker inducer of CYP3A4 while having similar efficacy to Rifampicin.
Rifampicin has minimal interaction with Azathioprine
Rifampicin increases Prednisolone Clearance, reducing its drug levels. Hence Prednisolone may need to be increased.
Isoniazid Interactions
Isoniazid is a weak CYP inhibitor. Increase in Drug levels of Tacrolimus, Cyclosporine, Sirolimus are usually not significant. There is no interaction with antiproliferatives (MMF and Azathiaprime) However there are increased rates of hepatotoxicity and leucopenia. It is important to monitor for these side-effects.
Reference
Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
· Rifampicin and immunosuppressive medications interaction
As cyclosporine, tacrolimus, sirolimus, MMF, and prednisone are all effective enzyme inducers, rifampicin can significantly reduce their levels or effects by inducing the cytochrome P450 CYP3A and, to a lesser extent, CYP2C enzymes.
· Rifampicin induces CYP3A4 over a number of days, peaking one week after the drug is started. Following the usage of rifampin, it is advised to 3-5 fold increase the dose of CNI or rapamycin while closely monitoring the serum level.
· No significant interactions exist between rifampicin and azathioprine.
Isoniazid :
Regularly monitor whole blood cyclosporine levels to ensure optimal therapy. Several drugs have been shown to alter the distribution of cyclosporine by altering hepatic metabolism. Rifampicin is a potent enzyme inducer which increases the clearance of cyclosporine.
Rifampicin is a potent CYP3A4 inducer, increasing sirolimus clearance approximately 5.5-fold and decreasing peak concentration (C max ) by 71%.
The risk of transplant rejection increases if serum sirolimus levels are not carefully controlled. This interaction should be taken into account when rifampicin or other drugs that affect pregnane X receptor activity are co-administered with mycophenolate mofetil.
Rifampicin significantly reduces tacrolimus levels despite several cytochrome P450 inhibitors
References :
1-Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O’Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A.Clin Infect Dis. 2016 Oct 1;63(7):e147-e195. doi: 10.1093/cid/ciw376. Epub 2016 Aug 10.PMID: 27516382 Free PMC article.
2-Saudi J Kidney Dis Transplant . 2011 Jan;22(1):112-5
3- Maarten Naesens 1, Dirk R J Kuypers, Frank Streit, Victor W Armstrong, Michael Oellerich, Kristin Verbeke, Yves Vanrenterghem
4- Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC.Ann Pharmacother. 2000 Jan;34(1):27-31. doi: 10.1345/aph.19069.PMID: 10669182
Rifampicin
· Its strong enzyme inducer affecting both cytochrome P450 CYP3A and to a lesser extent CYP2C and this led to decrease blood levels of tacrolimus, cyclosporin, sirolimus and MMF. Dose of CNI need to be increased 3-5 folds after starting rifampicin and this effect is delayed in onset usually reach peak at the end of 1st week.
· No effect on azathioprine.
INH
· This is controversy, INH is weak enzyme inhibitor with almost no effect in tacrolimus but maybe cyclosporine.
· Regarding MMF, azathioprine levels it has no effect but its hepatotoxicity and myelosuppression effect leads to stoppage of both MMF and azathioprine at 1st 6 weeks after starting treatment.
· Steroids causes reduction of therapeutic level of INH from 20-35% with no proven clinical significance.
References
Scenario 2
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin
Tacrolimus : Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.
Cyclosporine : Rifampin, a potent enzyme inducer, has been demonstrated to increase cyclosporine clearance.
Sirolimus : rifampicin is a strong inducer of CYP3A4, it increases the clearance of sirolimus approximately 5.5fold and decreases the maximum concentration (C max ) by 71%.
Azathioprine : The metabolism of Azithromycin can be increased when combined with Rifampicin.
Mycophenolate Mofetil : Long–term rifampin therapy caused a more than twofold reduction in dose–corrected mycophenolic acid (MPA) exposure (dose–interval area under the concentration curve from 0 to 12 hours [AUC0–12]) when administered simultaneously in a heart–lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout.
Prednisone : rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues (area under the plasma concentration time curve) by 66%. The effectiveness of prednisolone may be considerably reduced when rifampicin and prednisolone are used in combination.
———————————————————————
INH cytochrome p 450 inhibitor
Tacrolimus: will decrease the level of Tacrolimus but insignificant
Cyclosporine: There were no significant changes in cyclosporine pharmacokinetic parameters including cyclosporine trough levels, total cyclosporine exposure and cyclosporine clearance before and 2 weeks after instituting INH prophylaxis.
Sirolimus Isoniazid can increase the blood levels of sirolimus protein-bound. This may increase side effects such as mouth sores and inflammation, nausea, diarrhea, vomiting, abdominal pain, decreased appetite, increased blood sugar, rash, hair loss, lung or breathing problems, and impaired bone marrow function resulting in low numbers of different types of blood cells.
Azathioprine Common interactions include hepatitis among females and pancytopenia among males.
Mycophenolate mofetil Isoniazid and Mycophenolate mofetil. Common interactions include blood creatinine increased among females and bone marrow toxicity among males.
Prednisone prednisone cause significant decrease in plasma isoniazide consecration by inhanced the renal clearance in slow and rapid inactivator.
Reference
Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers
M F Hebert 1 , R M Fisher, C L Marsh, D Dressler, I Bekersky
Rifampin and Ansamycin Interactions with Cyclosporine After Renal Transplantation
Mr. Chris Vandevelde B.Sc., Pharm., Ms. Andria Chang B.Sc., Pharm., Dr. Denis Andrews Pharm.D., Dr. Wayne Riggs Ph.D., Dr. Peter Jewesson Ph.D.
Drug interaction between rifampicin and sirolimus in transplant patients
BT Ngo, M Pascoe, Delawir Kahn
Transplant Unit, Department of Surgery and Medicine and the Medical Research Council Liver Research Centre, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Drug interaction between mycophenolate mofetil and rifampin: Possible induction of uridine diphosphate-glucuronosyltransferase
Dirk R. J. Kuypers PhD, Geert Verleden PhD, Maarten Naesens MD, Yves Vanrenterghem PhD
Rifampicin reduces effectiveness and bioavailability of prednisolone
W A McAllister, P J Thompson, S M Al-Habet, H J Rogers
Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients
K Sud 1 , T Muthukumar, B Singh, S K Garg, H S Kohli, V Jha, K L Gupta, V Sakhuja
Isoniazid and Azathioprine drug interactions – a phase IV clinical study of FDA data
Isoniazid and Mycophenolate mofetil drug interactions – a phase IV clinical study of FDA data
INTERACTIONS WITH RIFAMPICIN:
INTERACTIONS WITH INH:
Drug interactions
Rifampicin
Rifampicin will induce cytochrome P450 and p-glycoprotein thus would cause;
· Low level of CNI(cyclosporine and tacrolimus)
· Low level of mTOR and prednisolone
· NO effect on MMF and AZA.
Isoniazid
INH is inhibitor of cytochrome P450 and thus may causes;
· Increases level of CNI and Sirolimus but its effect in not significant.
· Additive effect of Cytopenia when patients are on antimetabolites like MMF and AZA.
Rifampicine interaction with:
1. Tacrolimus, cyclosporine, sirolimus and prednisolone:
2. MMF: clinically relevant interaction between rifampicine and MMF. Long term Rifampicine therapy causes more than 2 fold reduction in dose – corrected MPA exposure dose. Failure to clinically recognize drug interaction could clinically to MPA underexposure and loss of clinical efficacy.
3. Azathioprine: no interaction with rifampicine
INH interaction with
1. CNI, zathioprine and MMF: No interaction
2. Prednisolone: Prednisolone decrease the level of INH due to decreased renal clearance of INH.
References:
1. T. Ngo, M. Pascoe, Delawir Kahn, Drug Interaction between Rifampicin and Sirolimus in Transplant Patients
2. Drug interaction between MMF and rifampicine.Clinical Pharmcology &Therapeutics (2005) 78, 81-88
3. GR Sharma , effect Agents of prednisolone and rifampicine on INH metabolism in slow and rapid inactivators of INH, Antimicrob Chemother 1980 Nov, 18(5)661-666
Drug interactions
Rifampicin is a potent cytochrome P 450 and p-glycoprotein inducer hence will reduce the levels of CNI and MTOR inhibitors. It also interferes with the metabolism of corticosteroids.Thus will lead to low levels of cyclosporine, tacrolimus, sirolimus and prednisolone.
Rifampicin and antimetabolites (MMF and azathioprine) doesn’t affect its metabolism whoever concomitant use may worsen adverse events like cytopenias.
Isoniazid is an inhibitor of cytochrome P450 thus it will increase the levels of tacrolimus, cyclosporine and sirolimus however this effect is not significant.
Isoniazid also cause cytopenias hence will worsen cytopenia caused by MMF and azathioprine if given concurrently.
References
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Bogdan Marian Sorohan, Gener Ismail, Dorina Tacu, Bogdan Obris, Gina Ciolan, Costin Gîngu, Ioanel Sinescu and Cătălin Baston.
Short and sweet
RIFAMPICIN is a potent inducer of several drug-metabolizing enzymes as well as P-glycoprotein (P-gp) multidrug efflux transporters, which can lead to significant reductions in concentrations and therapeutic failure of other drugs. Drug interactions result from the ability of rifampin to induce cytochrome P450 CYP3A metabolism (and to a lesser extent CYP2C) and glucuronidation, thereby accelerating drug excretion. Rifampin also increases intestinal P-gp mediated drug efflux, thereby reducing gastrointestinal absorption of drugs that are P-gp substrates.
Thus RIFAMPICIN decreases levels of TACROLIMUS and to overcome that the dose of tacrolimus should be increased to at least three to five folds.
Decreases level CICLOSPORIN AND SIROLIMUS
Azathioprine No effect
MYCOPHENOLATE
The interaction is less pronounced however long term use can lead to lower MMF levels
PREDNISONE
Overall, rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues (area under the plasma concentration time curve) by 66%. The effectiveness of prednisolone may be considerably reduced when rifampicin and prednisolone are used in combination.
INH
it can increase level of tacrolimus and ciclosporin and Sirolimus leading to nephrotoxicity
No effect on AZA and MMF
it can increases bone marrow suppressive effect when used in combination with AZA
Yes, I note that
-Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, and enhance immunosuppression metabolization. Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and increases glucocorticoids metabolization, and azathioprin which increases the risk of rejection.
-Therefore:
MMF:
References:
1- Sorohan BM et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041.
2- Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther. 2005 Jul;78(1):81-8
Thank you.
Does INH have an additive effect on the bone marrow?
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
Rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus).
Rifampicin usage decrease the levels of mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .
Rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Tacrolimus : Rifampicin decrease level of tacrolimus,
Cyclosporine: Rifampicin decrese level of cyclosporine
Sirolimus : Rifampicin decrese level of sirolimus .
Azathioprine : no effect.
Mycophenolate Mofetil : no effect
Prednisone :Rifampicin affect glucocorticoids metabolization (may increase level )
Isoniazid
INH inhibit CP450 3A4 inhibitor and monoamine oxidases.
Therefore, it will increase the level of CNI, mTOR inhibitors.
Steroids decreases the level of INH.
INH has significant adverse effect cytopenia and hepatotoxicity, co-administration with antimetabolites may augment this effect.
Tacrolimus: INH increase level of tacrolimus.
Cyclosporine: INH increase level of cyclosporine .
Sirolimus: INH increase level of sirolimus
Azathioprine: no change .
Mycophenolate Mofetil: no change.
Prednisone: may decrease level of INH.
REFERENCES
1.Subramanian, A.K.; Theodoropoulos, N.M. Mycobacterium Tuberculosis Infections in Solid Organ Transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation. Clin. Transplant. 2019, 33, e13513.
2. Meije, Y.; Piersimoni, C.; Torre-Cisneros, J.; Dilektasli, A.G.; Aguado, J.M. Mycobacterial Infections in Solid Organ Transplant Recipients. Clin. Microbiol. Infect. 2014, 20 (Suppl. 7), 89–101
3.Aguado, J.M.; Torre-Cisneros, J.; Fortún, J.; Benito, N.; Meije, Y.; Doblas, A.; Muñoz, P. Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin. Infect. Dis. 2009, 48, 1276–1284.
4.Bolt, H.M. Rifampicin, a Keystone Inducer of Drug Metabolism: From Herbert Remmer’s Pioneering Ideas to Modern Concepts. Drug Metab. Rev. 2004, 36, 497–509.
5.Nakada, Y.; Yamamoto, I.; Kobayashi, A.; Mafune, A.; Yamakawa, T.; Matsuo, N.; Tanno, Y.; Ohkido, I.; Yamamoto, H.; Yokoyama, K.; et al. Acute Vascular Rejection during Antituberculosis Therapy in a Kidney Transplant Patient. Nephrology 2014, 19 (Suppl. 3), 27–30.
6. Chuang, H.-W.; Chung, T.-L.; Lee, P.-T.; Wang, J.-S. Acute Antibody-Mediated Rejection with Graft Loss during Anti-Tuberculosis Therapy in Kidney Transplantation. Kaohsiung J. Med. Sci. 2015, 31, 437–439. Chenhsu, R.Y.; Loong, C.C.; Chou, M.H.; Lin, M.F.; Yang, W.C. Renal Allograft Dysfunction Associated with Rifampin-Tacrolimus Interaction. Ann. Pharmacother. 2000, 34, 27–31.
Thank you.
Does INH have an additive effect on the bone marrow?
2. What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus (1-3)
– Rifampin is a potent inducer of cytochrome P450 CYP3A metabolism (and to a lesser extent CYP2C) and glucuronidation and in doing so accelerates drug excretion.
– Rifampin also increases intestinal P-glycoprotein (P-gp) mediated multidrug efflux transporter and by such means reduces GI absorption of drugs that are P-gp substrates like tacrolimus.
– Tacrolimus is metabolized by CYP3A5 and CYP3A4 in the liver and small intestine.
– Rifampin induces both intestinal and hepatic metabolism of tacrolimus through induction of CYP3A4 and p-glycoprotein in both the liver and small bowel.
– the serum concentration of tacrolimus can increase when it is co-administered with INH since INH alters tacrolimus metabolism resulting in increased tacrolimus trough levels
Cyclosporine (1-3)
– Rifampin is a potent inducer of cytochrome P450 CYP3A metabolism (and to a lesser extent CYP2C) and glucuronidation and in doing so accelerates drug excretion.
– Rifampin also increases intestinal P-glycoprotein (P-gp) mediated multidrug efflux transporter and by such means reduces GI absorption of drugs that are P-gp substrates like tacrolimus.
– Tacrolimus is metabolized by CYP3A5 and CYP3A4 in the liver and small intestine.
– Rifampin induces both intestinal and hepatic metabolism of tacrolimus through induction of CYP3A4 and p-glycoprotein in both the liver and small bowel.
– Metabolism of cyclosporine can be decreased when co-administered with INH
Sirolimus (4, 5)
– CYP3A is essential for up to 90% of CNI (tacrolimus, cyclosporine) and mTORi (sirolimus) metabolism.
– Rifampicin is a potent inducer of CYP3A4, hence it increases the clearance of sirolimus by ~5.5fold and decreases the Cmax (maximum concentration) by 71%. This in effect increases the risk of graft rejection if the sirolimus dose is not adjusted accordingly.
– INH alters sirolimus drug metabolism resulting in an increase in the sirolimus trough levels
Azathioprine
– Rifampicin increases the metabolism of azathioprine
– Metabolism of azathioprine can be decreased when co-administered with INH
Mycophenolate Mofetil (MMF) (6)
– MMF is a cornerstone immunosuppressive agent in SOT.
– Rifampicin induces the expression of a number of drug metabolism-related genes involved in cytochromes (CYP3A4), multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), monoamine oxidases, glutathione S-transferases, uridine phosphate-glucuronosyltransferases (UGT). Drugs depending on these enzymes for their metabolism are prone to drug interactions with rifampicin when administered together.
– Rifampin use simultaneously induces renal, hepatic and GI UGT and organic anion transporters leading to functional inhibition of enterohepatic recirculation of MMF.
– Metabolism of MMF can be decreased when co-administered with INH
Prednisone (7, 8)
– Rifampicin is an inducer of enzymes responsible for hepatic drug metabolism.
– Rifampicin increases the plasma clearance of prednisone by
~45% and reduces the amount of drug available to the tissues (i.e., AUC) by 66%.
– this therefore implies that the effectiveness of prednisone is reduced when it is co-administered with rifampicin
– INH alters metabolism of prednisone hence increasing the prednisone levels
– Prednisone decreases plasma INH concentrations in both slow and rapid inactivators
– Prednisone increases the rate of INH acetylation in slow inactivators only
– Prednisone enhances renal clearance of INH in both slow and rapid inactivators
References
1. Hebert MF, Fisher RM, Marsh CL, Dressler D, Bekersky I. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. Journal of clinical pharmacology. 1999 Jan;39(1):91-6. PubMed PMID: 9987705. Epub 1999/02/13. eng.
2. Charfi R, Ben Sassi M, Gaïes E, Bacha M, Jebabli N, El Jebari H, et al. Early interaction between tacrolimus and rifampin. La Tunisie medicale. 2019 May;97(5):722-5. PubMed PMID: 31729747. Epub 2019/11/16. eng.
3. Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin, rifabutin, and rifapentine drug interactions. Current medical research and opinion. 2013 Jan;29(1):1-12. PubMed PMID: 23136913. Epub 2012/11/10. eng.
4. Sehgal SN. Rapamune (Sirolimus, rapamycin): an overview and mechanism of action. Therapeutic drug monitoring. 1995 Dec;17(6):660-5. PubMed PMID: 8588237. Epub 1995/12/01. eng.
5. Ngo B, Pascoe M, Kahn D. Drug interaction between rifampicin and sirolimus in transplant patients. Saudi Journal of Kidney Diseases and Transplantation. 2011 January 1, 2011;22(1):112-5.
6. Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clinical pharmacology and therapeutics. 2005 Jul;78(1):81-8. PubMed PMID: 16003296. Epub 2005/07/09. eng.
7. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. British medical journal (Clinical research ed). 1983 Mar 19;286(6369):923-5. PubMed PMID: 6403136. Pubmed Central PMCID: PMC1547305. Epub 1983/03/19. eng.
8. Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrobial agents and chemotherapy. 1980 Nov;18(5):661-6. PubMed PMID: 7447424. Pubmed Central PMCID: PMC284072. Epub 1980/11/01. eng.
https://www.webmd.com/interaction-checker/default.htm
https://go.drugbank.com/drugs/DB00951
Thank you.
Rifampicin is a potent cytochrome CYP3A enzyme inducer, so it tends to reduce the level of drugs metabolized by this enzyme.
Tacrolimus
Rifampicin reduces the level of Tacrolimus (severe interaction).
INH doesn’t interact with Tacrolimus.
Cyclosporin
Rifampicin reduces the level of Ciclosporin (severe interaction).
INH doesn’t interact with Ciclosporin.
Sirolimus
Rifampicin reduces the level of Sirolimus (severe interaction).
INH doesn’t interact with Sirolimus.
Azathioprine
Rifampicin doesn’t have interactions with azathioprine.
INH doesn’t have interactions with Azathioprine. However, INH side effects include hepatotoxicity and leucopenia which can exacerbates side effects of Azathioprine.
Mycophenolate Mofetil
Rifampicin reduces the level of Mycophenolate (severe interaction).
INH doesn’t interact with Mycophenolate. However, INH side effects include hepatotoxicity and leucopenia which can exacerbates side effects of Mycophenolate.
Prednisone
Rifampicin is predicted to decrease the exposure to Prednisolone. Manufacturer advises monitor and adjust dose. (moderate severity).
INH doesn’t interact with prednisolone.
Reference:
BNF
Uptodate
Thank you.
Does INH have an additive effect on the bone marrow?
As a strong CYP3A4 inducer, Rifampicin decreases the serum concentration of Sirolimus, Tacrolimus and cyclosporin, requiring increasing the dose.
on the other hand, INH is a weak CYP3A4 inhibitor that increases cyclosporin, tacrolimus and cyclosporin levels.
CycloSPORINE may enhance the neuroexcitatory and or seizure-potentiating effect of Prednisolone.
Rifampicin may decrease serum concentrations of the active metabolites of Mycophenolate, Specifically, mycophenolic acid (MPA), conc. Maybe decrease.
————–
**Lexicomp drug interactions
Thank you. This is a very short answer
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin :
Rifampicin, a potent inducer of cytochrome P450 3A4 .
rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus).Rifampicin reduce the level of prednisolone and increase its clearance.
when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. Additionally, after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target .
MMF and AZA : no interaction.
INH : is an enzyme inhibitor
INH increase the level of Tacrolimus and sirolimus.
INH has no interaction with cyclosporine, MMF,AZA.
INH increase the level of prednisolone, and prednisolone can decrease the concentration of INH.
Thank you.
Does INH have an additive effect on the bone marrow?
INH can cause autoimmune hemolytic anemia and pure red cell aplasia.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Tacrolimus
Cyclosporine
Sirolimus
Azathioprine
Mycophenolate Mofetil
Prednisone
Rifampicin
Rifampicin is enzyme inducer CYP 3A4
It will reduce the drug levels of –
· Tacrolimus
· Cyclosporine
· Sirolimus
· MMF
· No interaction with Azathioprine
· It can reduce levels of prednisolone
Isoniazid- INH
Lwin PW, Htun YY, Myint AK, Swe HK. Posttransplantation tuberculosis management in terms of immunosuppressant cost: a case report in Myanmar. Korean J Transplant. 2021 Mar 31;35(1):48-52
Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med. 1984 Aug;144(8):1667-71.
Thank you.
Does INH have an additive effect on the bone marrow?
It can cuse eosinophilia, neutropenia, thrombocytopenia, autoimmune hemolytic anemia, pure red cell aplasia (PRCA), and sideroblastic anemia
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Very short
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
· Tacrolimus
· Cyclosporine
· Sirolimus
· Azathioprine
· Mycophenolate Mofetil
· Prednisone
Rifampicin:
The Rifamycins (Rifampicin and Rifabutin) are strong inducers of enzyme CYP3A4. They are associated with increased metabolism, and hence reduced drug levels of calcineurin inhibitors (cyclosporin and Tacrolimus) and mTOR inhibitors (sirolimus and everolimus) thereby warranting an increase in the doses of these medications (1). Hence dose of Cyclosporin, Tacrolimus, and sirolimus needs to be increased at time of initiation of rifampicin (dose increase required in range of 2-5 times, even upto 10 times), and regular monitoring of trough levels is required. At time of discontinuing rifampicin, the doses need to be reduced accordingly. Rifabutin is a less potent enzyme inducer, hence the increase in dose required would be lower as compared to rifampicin use.
Effect of Rifampicin on Mycophenolate mofetil (MMF) is less pronounced, but nevertheless is associated with lower MMF levels (induction of mycophenolic acid glucuronidation via uridine diphosphate-glucuronosyltransferase, and reduced enterohepatic recirculation).Tthis combination should be avoided as per the manufacturer (1,2).
There is no discernible effect of rifampicin use on azathioprine.
Rifampicin use also reduces the levels of steroids (CYP3A4 induction), hence the dose of steroids should be increased to 2 -times (1,3).
Isoniazid:
Although isoniazid is a CYP3A4 enzyme inhibitor, leading to increased levels of cyclosporin, tacrolimus, everolimus, and sirolimus, the effect on these drugs is not significant (1). There is no effect of isoniazid on MMF and azathioprine. But concomitant use of isoniazid with antimetabolites can pronounce the side effects like leukopenias. Use of Steroids and Isoniazid together is associated with reduced levels of isoniazid (4).
References:
1. Sparkes T, Lemonovich TL; AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13510. doi: 10.1111/ctr.13510. Epub 2019 Apr 23. PMID: 30817021.
2. Naesens M, Kuypers DR, Streit F, Armstrong VW, Oellerich M, Verbeke K, Vanrenterghem Y. Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients. Clin Pharmacol Ther. 2006 Nov;80(5):509-21. doi: 10.1016/j.clpt.2006.08.002. PMID: 17112807.
3. Monostory K. Metabolic Drug Interactions with Immunosuppressants. Organ Donation and Transplantation – Current Status and Future Challenges [Internet]. 2018 Jul 25; Available from: http://dx.doi.org/10.5772/intechopen.74524
4. Yew WW. Clinically significant interactions with drugs used in the treatment of tuberculosis. Drug Saf. 2002;25(2):111-33. doi: 10.2165/00002018-200225020-00005. PMID: 11888353.
I like this, well done
isoniazid:
Although isoniazid is a CYP3A4 enzyme inhibitor, leading to increased levels of cyclosporin, tacrolimus, everolimus, and sirolimus, the effect on these drugs is insignificant. There is no effect of isoniazid on MMF and azathioprine. But concomitant use of isoniazid with antimetabolites can pronounce the side effects like leukopenias. Steroids and Isoniazid are associated with reduced levels of isoniazid.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
INH (Isoniazid) (It is an enzyme inhibitor – CYP3A4)((Decrease Metabolism of):
-INH => will increase the levels of tacrolimus.
-Cyclosporine => No interaction
-INH => will increase the levels of sirolimus
-AZA=> No interaction
-MMF => No interaction
-Prednisone=> INH will increase the level of prednisone and prednisone can reduce the drug concentration of INH
Rifampicin: (It is an enzyme inducer – CYP3A4)(increase Metabolism of):
– Rifampicin => will reduce the levels of tacrolimus
-Rifampicin => will reduce the level of cyclosporine
-Rifampicin => will reduce the level of sirolimus
-AZA => No interaction
-MMF => No interaction
– Rifampicin will reduce the levels of prednisone(Rifampicin increases prednisolone clearance by around 45% and reduce the amount of drug available to the tissues by around 66%)
References:
*Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
*Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
[
*Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
Thank you
Rifampicin is a strong inducer of CYP3A4, leading to increased metabolism
calcineurin inhibitors, mammalian target of rapamycin inhibitors, mycophenolate mofetil,
and corticosteroids.
Rifabutin is a less potent cytochrome inducer.
The dose of calcineurin inhibitors should be increased (3–5 times), but this results in
higher .
Drug levels need to be closely monitored at the initiation of TB therapy, after the
discontinuation of rifampicin or rifabutin, or with any adjustment of immunosuppressant
dosing.
INH:
CS.
May increases CS level ,risk of adverse effect.
CNI
No effect.
MMF .
No effect..
mTors.
No effects
Reference :
1-Risk of T.B in transplant recipient and donor.shttps://erj.ersjournals.com/content/40/4/990
.
Thank you
-Rifampicin leads to expression of drug metabolism-related genes involved in multidrug resistance ;P-glycoprotein &multidrug resistance proteins 1 and 2.Also,it induces:
. Cytochrome P450 [CYP] 3A4).
.Uridine diphosphate-glucuronosyltransferases.
. Monoamine oxidases.
. Glutathione S -transferases.
Drugs involving these enzymes in their metabolism are vulnerable to drug-drug interactions when used with rifampin.
– Rifampicin decreases the levels of CNI, (mTOR) inhibitors , and affects glucocorticoids metabolism; increasing clearance by 49% and tissue availability by 66%.
INH through inhibiting CP450 3A4 inhibitor and monoamine oxidases, will increase the level of CNI, mTOR inhibitors.
Steroids decrease INH level with unclear mechanism.
INH has hepatotoxicity and cytopenia, so its use with antimetabolites may aggravate these effects.
One of the challenges of treating TB in KTRs is drug–drug interactions:
1. Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
2. Specifically, rifampicin usage decreases the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection(1).
3. INH will increase the level effect of CNIs and mTORi by affecting hepatic/intestinal enzyme CYP3A4 metabolism(2).
4. Plasma concentrations of isoniazid may be reduced during coadministration with corticosteroids. The mechanism of interaction has not been established, but may involve enhanced hepatic and/or renal elimination of isoniazid. In a study of 26 patients with tuberculosis given isoniazid 10 mg/kg/day, investigators reported a 23% reduction in plasma isoniazid concentrations for slow acetylators and a 38% reduction for rapid acetylators following the administration of a single 20 mg dose of prednisolone. The clinical significance of this potential interaction is unknown. Prednisolone did not appear to alter the clinical response to isoniazid treatment in the study. Nonetheless, it may be advisable to monitor patient response to isoniazid more closely during concomitant corticosteroid therapy and adjust the isoniazid dosage if necessary(3,4).
Drug-Drug interaction(Rif & INH plus the followings)(2,5)
Tacrolimus and Cyclosporine:
a) The coadministration with rifamycins, particularly rifampin, may decrease the blood concentrations and pharmacologic effects of cyclosporine and tacrolimus. The mechanism probably involves reduced absorption as well as accelerated clearance of CNIs due to induction of both intestinal P-glycoprotein drug efflux pumps and hepatic/intestinal CYP450 3A4 isoenzymes by rifamycins.
b) Isoniazid may decrease serum cyclosporine and tacrolimus concentrations. The mechanism is induction of hepatic CYP450 3A4 metabolism by isoniazid.
5. Sirolimus:
a) Coadministration with rifampicin, potent inducers of CYP450 3A4 and/or P-glycoprotein may significantly decrease the plasma concentrations and pharmacologic effects of sirolimus. The mechanism probably involves reduced absorption as well as accelerated clearance of sirolimus due to induction of both intestinal P-glycoprotein drug efflux transporter and hepatic/intestinal CYP450 3A4 isoenzymes.
b) INH will increase the level or effect of sirolimus by affecting hepatic/ intestinal enzyme CYP3A4 metabolism.
6. Azathioprine
a) No interactions were found between the drug and rifampicin.
b) No interactions were found between the drug and INH.
7. Mycophenolate Mofetil:
a) Coadministration with rifampin may decrease the plasma concentrations of mycophenolic acid (MPA). The mechanism is thought to involve induction of MPA glucuronidation via gastrointestinal and hepatic uridine diphosphate glucuronosyltransferase (UGT) isozymes and reduction of enterohepatic recirculation of MPA metabolites secondary to competitive inhibition of multidrug resistance-associated protein 2 (MRP2)-mediated biliary excretion by rifampin.
b) No interactions were found between the drug and INH.
8. Prednisone
a) Rifampicin may induce the hepatic metabolism of corticosteroids, possibly reducing their therapeutic effect. The elimination half-life of corticosteroids has been shown to be reduced by up to 45% when rifampin is coadministered.
b) Plasma concentrations of isoniazid may be reduced during coadministration with corticosteroids. The mechanism of interaction has not been established, but may involve enhanced hepatic and/or renal elimination of isoniazid.
References
1. Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
2. Medscape online.
3. Sarma G, Kailasam S, Nair NG, Narayana AS, Tripathy SP “Effect of prednisonlone and refampin on isoniazid metabolism in slow and rapid inactivators of isoniazid.” Antimicrob Agents Chemother 18 (1980): 661-6
4. Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, MacIntyre I, Park BK “Effect of isoniazid on vitamin D metabolism and hepatic monooxygenase activity.” Clin Pharmacol Ther 30 (1981): 363-7
5. Drugs.com for professional https://www.drugs.com
Thank you Safi
Please reflect on your statement “No interactions were found between the drug and INH”.
Drug-induced neutropenia can occur in association with anti-TB .
The incidence rate of agranulocytosis due to anti-tuberculosis drugs was estimated at 0.06% . In the context of anti-tuberculosis therapy, neutropenia is recognized as being most frequently happening due to isoniazid , but it can be related to rifampicin , ethambutol and streptomycin prescription .
It is obvious that the haematological side effects of anti-TB ( agranulocytosis and neutropenia) can be aggravated by the adverse effects of anti metabolites( AZA and MMF).
Reference
CASE REPORT Leukopenia Induced by Anti-Tuberculosis Treatment
Belloumi N, Ben Bdira B, Bachouche I, Kacem M, Chermiti Ben Abdallah F and Fenniche S
DOI:10.23937/2378-3516/1410093
Anti-TB drugs and their side effects
First line anti MTB includes, rifampicin, INH , pyrazinamide, ethambutol
The mean concern about medications in general including anti-MBT drugs includes efficacy, safety, drug-drug interaction, side effects, toxicity, cost
Use of anti-TB medication after SOT there is concern about the drug interactions with other immunosuppressive medications in particular CNI ( Tacrolimus, cyclosporine ), m TOR inhibitors like sirolimus and everolimus, antimetabolites ( azathioprine and MMF ), Steroids
RIFAMPICIN
Rifampicin considers the first-line anti-TB with high potency for sterilization of mycobacteria through its bactericidal effects inhibit protein synthesis by blocking mRNA transcription and synthesis; hepatically metabolized. But there is concern about its hepatotoxicity as it acts as an enzyme inducer through the cytochrome 450, CYP3A4, and rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. and can reduce the level of CNI, sirolimus, and everolimus even to undetectable levels so we need to increase the dose of tacrolimus or Cyclosporine by 3-5 folds ( sometimes will give TID dose ) with close monitoring by trough level, also need frequent LFT monitoring for transaminitis weekly in the first two months then every month, rifabutin as an alternative can be used and it’s more tolerated compared to rifampicin, rifabutin has a lower cytochrome inducer effect Dose: rifampicin 600 mg/d; rifabutin 300 mg/d.
Sirolimus follows the same for CNI and needs dose adjustment with frequent monitoring
.
No interaction with azathioprine,
MMF and rifampicin lead to reduced the level of MMF due to interaction with enterohepatic circulation.
INH
Isoniazid and rifamycins can cause drug-induced hepatitis, and the previously used combination of rifampicin/pyrazinamide can cause severe liver toxicity(3). So needs close monitoring twice weekly in the first two weeks then weekly in the first two months, consider discontinuation if liver enzymes increased by 5 folds from baseline.
INH and steroids
prednisolone caused a significant decrease in the plasma isoniazid concentrations in both slow and rapid inactivators (2).due to increased renal clearance of isoniazid in both slow and rapid inactivators and augmented the rate of acetylation of isoniazid in slow inactivators but concomitant administration of rifampin had considerably modified the prednisolone effect on the disposition of isoniazid.
MMF and azathioprine , sirolimus , CNI ( NONE ) .
References
1. Pennington KM, Kennedy CC, Chandra S, Lauzardo M, Brito MO, Griffith DE, Seaworth BJ, Escalante P. Management and diagnosis of tuberculosis in solid organ transplant candidates and recipients: Expert survey and updated review. J Clin Tuberc Other Mycobact Dis. 2018 Apr 10;11:37-46.
2. Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother. 1980 Nov;18(5):661-6
3. . Aguado JM, Torre-Cisneros J, Fortun J. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish society of infectious diseases and clinical microbiology. Clin Infect Dis. 2009;48(9):1276–1284. [PubMed] [Google Scholar]
Excellent
Severity classification of drug-drug interaction is as follows(1)
Rifampicin interactions with(2):
Tacrolimus/Cyclosporine
Sirolimus
Azathioprine:
Mycophenolate Mofetil:
Prednisone:
INH interactions with(2)
Prednisone:
Tacrolimus/Cyclosporine/Sirolimus/Azathioprine/Mycophenolate Mofetil
References:
Thank you
⭐ Rifampin is an enzyme inducer of CYT P 3A4 that is important in metabolism of CNI and mTORi , so it’s concomitant use decrease trough level of cyclosporin, tacrolimus and sirolimus, so increasing their dose by 3-5 folds is indicated to decrease risk of rejection.
Also it decrease the concentration of steroids by 45%, so doubling of steroid dose is usually required to minimize risk of rejection.
However, it inhibits the entro-hepatic circulation so increase the concentration of MMF
⭐ INH is enzyme inhibitors so may increase concentration of CNI and mTORi
⭐ INH can cause myelosuppression, so it can augment the adverse effects of MMF when used together as causing leukopenia.
Thank you Mai
What about the rest of questions?
Drug interactions between Rifampicin against immunosuppressants medication
Rifampicin is a potent Cyt 450 inducer so enhances the metabolism of the above medications.
Drug interactions between INH against immunosuppressants medication
References
[1] Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
[2] Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
[3] Gervasini G, Benítez J, Carrillo JA. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. European Journal of Clinical Pharmacology. 2010;66:755-774. DOI: 10.1007/s00228-010-0857-7
Thank you
Rifampicin:
All the rifamycins are strong inducers of CYP3A4
Both rifampicin and rifabutin decrease the plasma levels of calcineurin and mTOR inhibitors, leading to acute graft rejection
Mycophenolate is metabolized into mycophenolic acid, which undergoes glucuronidation by uridine diphosphate glucuronosyltransferases (UGTs) in the liver, kidney, and intestine to its inactive metabolite (7-O-glucuronide).
Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by UGTs and reduces enterohepatic recirculation and absorption of mycophenolic acid.
Also one metabolite of MMF, acyl-glucuronide, gets accumulated and attains higher blood level in presence of rifampicin, which may increase the toxicity or adverse effect
Isoniazid and ethambutol do not seem to interact with immunosuppressive agents.
Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
Thank you
Isoniazid: (It is an enzyme inhibitor – CYP3A4)
Rifampicin: (It is an enzyme inducer – CYP3A4)
Thank you very much for your reply
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin:
o A potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization
o Decreases the levels of CNIs (cyclosporine, tacrolimus), the mTOR inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization (also reduce the level), which increases the risk of rejection
o When a rifampicin-based regimen is used, CNIs and mTOR inhibitors levels should be closely monitored, the dose of CNIs and mTOR inhibitor should be increased between 3-5-folds and the glucocorticoid dose should be doubled during treatment and adjusted thereafter
o After the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target
o Rifampicin also reduce the concentration of active mycophenolate metabolite
o No direct interaction of rifampicin with azathioprine
INH:
There is no direct interaction with the above immunosuppressants but increase the risk of hepatotoxicity, neurotoxcity, and cytopenia that caused by other anti-tuberculous drugs
References
1. Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris ,ca˘, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
2. The Renal Drug Handbook, 5th edition, 2019.
Thank you very much for your reply
Rifampicin, induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2).
– Cytochromes (cytochrome P450 [CYP] 3A4).
– Uridine diphosphate-glucuronosyltransferases.
– Monoamine oxidases.
– Glutathione S -transferases.
Drugs that depend on these enzymes for their metabolism are prone to drug interactions when co-administered with rifampin.
– Rifampicin Potent inducer of cytochrome P450 3A4 and P-glycoprotein: its usage decrease the levels of CNI (cyclosporine, tacrolimus), (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection.
-Rifampin induce renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA that reduce drug exposure in heart-lung transplant recipient.
Isoniazid INH inhibit CP450 3A4 inhibitor and monoamine oxidases. Therefore, it will increase the level of CNI, mTOR inhibitors.
Steroids decreases the level of INH, mechanism is unclear.
INH has significant adverse effect cytopenia and hepatotoxicity, co-administration with antimetabolites may augment this effect.
References:
Sparkes, T, Lemonovich, TL. Interactions between anti-infective agents and immunosuppressants—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019; 33:e13510. https://doi.org/10.1111/ctr.13510
Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther. 2005 Jul;78(1):81-8. doi: 10.1016/j.clpt.2005.03.004. PMID: 16003296.
Excellent response. You mentioned previously Referred in case 1 to difference between Rifampicin and Rifabutin which is worth mentioning here because of the differential effect on Tacrolimus with similar antibiotic effect.
This is usually forgotten is the impact of Rifampicin on prednisolone. Rifampicin increases prednisolone clearance by around 45% and reduce the amount of drug available to the tissues by around 66%
Thank you Prof. for your comment
Rifabutin has similar efficacy to Rifampin, both drugs induce CP450 3A4, but Rifabutin is much less potent enzyme inducer, which make achieving therapeutic level of IS easier than Rifampin.
INH : it is enzyme inhibitors as it inhibits CYP3A4 , so increases the level of Tacrolimus, sirolimus prednisone, while it will not affect cyclosporine, MMF, AZA
Using INH with anti metabolite with aggravate cytopenia
Rifampicin: is a potent enzyme inducer as it activates CYP3A4 , so it decreases level of Tacrolimus, cyclosporine, and sirolimus with no effect on AZA and MMF
References:
*Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021 Jan;25(1):67-76. doi: 10.5005/jp-journals-10071-23439. PMID: 33603305; PMCID: PMC7874296.
Sorohan, B.M.; Ismail, G.; Tacu, D.; Obris ,ca˘, B.; Ciolan, G.; Gîngu, C.; Sinescu, I.; Baston, C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens 2022, 11, 1041. https://doi.org/10.3390/ pathogens11091041
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin: is a potent enzyme inducer of CYP3A4
Rifampicin causes a profound reduction in the serum levels of tacrolimus, cyclosporine, sirolimus, everolimus, and corticosteroids, thus high risk of graft rejection, so the dose should be increased 3-5 folds, with continuous blood level monitoring.
Isoniazid (INH): inhibits the cytochrome P450 system
References:
(1) Aguado JM, Silva JT, Samanta P, Singh N. Tuberculosis and Transplantation. Microbiol Spectr. 2016 Nov;4(6). doi: 10.1128/microbiolspec.TNMI7-0005-2016. PMID: 27809952.
(2) Sarma GR, Kailasam S, Nair NG, Narayana AS, Tripathy SP. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother. 1980 Nov;18(5):661-6. doi: 10.1128/AAC.18.5.661. PMID: 7447424; PMCID: PMC284072.
(3) UpToDate and Micromedex.
Thank you Dr Mohammad Alshaikh Hasan.
Well done. I could not understand the classification of Risk grading and difference between risk C,D, and X.
If used together, closely monitor mycophenolic acid levels and clinical response. I’m not sure that this is a routine practice for monitoring Mycophenolic acid level when combined with Rifampicin.
Therefore it’s worth mentioning Rifabutin as a replacement for Rifampicin with less enzyme inducer effect compared to Rifampicin.
Thank you Prof. Mohsen.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?Rifampcin and INH are both enzyme inducer for cytochromep450isoenzyme cyp3A4 can reduce BOTH CNI (TAC&cyclosporin ) and mTOR(sirolimus)
so need to increase CNI 3 to 5fold this takes several days to occur and peaks with a weak and also with mTOR
Rifampicin has been associated with rejection if combined with CNI or mTOR.
no interaction between INH& Rifampicin and Azathioprine
MMF reduce by rifampicin although MMF in the active T.B reduce or hold in the first 6 weeks
prednisolone reduce by rifampicin although this has been less well characterized
reference
UpToDate
I like your approach: “MMF in the active T.B reduce or hold in the first 6 weeks”.
Typing ‘Uptodate’ is not a good enough reference in a scientific write-up.
Rifampicin is a potent enzyme inducer of CYP3A4.
Rifampicin causes marked reduction in their serum levels tacrolimus, cyclosporine, m TOR and steroid.no interaction with azathioprine.
INH inhibits the cytochrome P450 system and acts as a mild monoamine oxidase inhibitor (MAO-I)
INH will increase the level or effect of tacrolimus and Sirolimus.
no effect on cyclosporin, azathioprine, MMF
I- Drug interaction between rifampicine and immune suppression: `
Rifampicine is a potent enzyme inducer of CYP3A4 which is the main enzyme involved in metabolism of tacrolimus , m TOR , MMF and steroid . so combination of those drugs with Rifampicine causes marked reduction in their serum levels , thus frequent trough drug level monitoring is required from starting treatment with rifampicine and for 2 weeks after stopping it,as its effect on CYP3A4 continue for 2 weeks after its sessation. A;so , the dose will need to be increase up to (2-5) folds
II- INH :inhibits both the cytochrome P450 and monoamine oxidase systems , so it will increase the level of tacrolimus and Sirolimus . But no interaction between INH and cyclosporine, azathioprine and mycophenolate
You have implied in your first paragraph that MMF levels might decrease when commenced on Rifampicin.
However, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Rifampin should be used with caution due to significant interactions between this class of drug and the calcineurin inhibitors and rapamycin (sirolimus). The rifamycins (especially rifampin) reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4, and the combination of a rifamycin with these drugs has been associated with the development of rejection . Rifamycins also reduce levels of glucocorticoids, although this has been less well characterized
●If rifampin is used, the dose of the calcineurin inhibitor or rapamycin should be increased approximately three- to fivefold, and serum concentrations should be monitored CYP3A4 induction by rifampin takes several days to occur, usually peaks within a week, and lasts for days to weeks
**the interaction of the anti-tuberculous drugs (Rifampicin and INH)
Rifampicin and Isoniazid (INT) (CYP3A4 Inducers (Strong))
may decrease the serum concentration of Tacrolimus -Cyclosporine – Sirolimus
Risk Rating D: Consider therapy modification
Severity Major
Reliability Rating Good
Patient Management Monitor closely for reduced Tacrolimus -Cyclosporine – Sirolimus
concentrations when combined with strong CYP3A4 inducers.
Tacrolimus -Cyclosporine – Sirolimus DOSES increases will likely be required to maintain adequate serum concentrations.
**Azathioprine-(Rifampicin and INH)
No interactions of Risk Level A or greater identified
**Mycophenolate / RifAMPin
Risk Rating D: Consider therapy modification
RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
Severity Major
Reliability Rating Good
Patient Management Avoid concurrent use of rifampin and mycophenolate when possible. If used together, closely monitor mycophenolic acid levels and clinical response. Mycophenolate doses may need to be increased.
**(MMF-INH)
No interactions of Risk Level A or greater identified.
**PredniSONE / (Rifampicin and INH)
Risk Rating C: Monitor therapy
CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE.
Severity Moderate
Reliability Rating Excellent
Patient Management Monitor for decreased prednisone effects if combined with a strong CYP3A4 inducer. Increases in prednisone dose may be required to maintain steroid effectiveness.
Reference
UpToDate
Lexicomp® Drug Interactions
You mention that MMF levels might decrease when commenced on Rifampicin. I have not heard that.
However, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
THANKS Prof. Ajay Sharma
NOTED
–Rifampicin is a strong inducer of CYTP3A4 increasing metabolism of CNI as Tac and cyclosporine, and mTOR inhibitors as Sirolimus , and mycophenolate mofetil and prednisolone .
For cyclosporine , Rifampicin also decreases the absorption of cyclosporine by inducing its metabolism by gut wall.
For MMF, Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by uridine diphosphate glucuronosyltransferases (UGTs) and reduces enterohepatic recirculation and absorption of mycophenolic acid also one metabolite of MMF, acyl-glucuronide, gets accumulates with rifampicin, which may increase the toxicity or adverse effects.
For azathioprine there was no interaction noted with Rifampicin
–INH inhibits the cytochrome P450 system and acts as a mild monoamine oxidase inhibitor (MAO-I)
INH will increase the level or effect of tacrolimus and Sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
INH did not show interaction with cyclosporine, azathioprine and mycophenolate
It may increase corticosteroid levels and its adverse effects,
Reference
-Anand M, Nayyar E, Concepcion B, Salani M, Schaefer H. Tuberculosis in kidney transplant recipients: A case series. World J Transplant. 2017;7(3):213-221
-Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP. Drug Interactions between Antimicrobial and Immunosuppressive Agents in Solid Organ Transplant Recipients. Indian J Crit Care Med. 2021;25(1):67-76.
-Medscape drug interactions
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
This is not a good enough reference in a scientific write-up:
Medscape interaction checker
Thanks Professor
Drug interactions between Rifampicin and INH against immunosuppressants medication
2. Rifampicin against Azathioprine and Mycophenolate;
3. INH against TAC/CyA/SIR;
4. INH against AZA/MYC;
References
[1] Shah RR, Smith RL. Addressing phenoconversion: The Achilles’ heel of personalized medicine. British Journal of Clinical Pharmacology. 2015;79:222-240. DOI: 10.1111/bcp. 12441
[2] Squassina A, Manchia M, Manolopoulos VG, Artac M, Lappa-Manakou C, Karkabouna S, Mitropoulos K, Del Zompo M, Patrinos GP. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics. 2010;11:1149-1167. DOI: 10.2217/pgs.10.97
[3] Gervasini G, Benítez J, Carrillo JA. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. European Journal of Clinical Pharmacology. 2010;66:755-774. DOI: 10.1007/s00228-010-0857-7
[4] Shah RR, Shah DR. Personalized medicine: Is it a pharmacogenetic mirage? British Journal of Clinical Pharmacology. 2012;74:698-721. DOI: 10.1111/j.1365-2125.2012.04328.x
[5] Sim SC, Kacevska M, Ingelman-Sundberg M. Pharmacogenomics of drug-metabolizing enzymes: A recent update on clinical implications and endogenous e
I like your well-referenced though a concise reply.
Rifampicin and immunosuppressive medications interaction
As cyclosporine, tacrolimus, sirolimus, MMF, and prednisone are all effective enzyme inducers, rifampicin can significantly reduce their levels or effects by inducing the cytochrome P450 CYP3A and, to a lesser extent, CYP2C enzymes. Rifampicin induces CYP3A4 over a number of days, peaking one week after the drug is started. Following the usage of rifampin, it is advised to 3-5 fold increase the dose of CNI or rapamycin while closely monitoring the serum level. No significant interactions exist between rifampicin and azathioprine.
Isoniazid and immunosuppressive medications interaction
Prednisolone may lower plasma concentrations of INH by an unidentified mechanism. In a trial involving 26 TB patients who were administered INH at a dose of 10 mg/kg/day, the administration of a single dose of 20 mg of prednisolone resulted in a 23% drop in plasma INH concentrations and a 38% reduction in plasma drug concentrations. Yet, it is unclear how this connection may manifest clinically.
Tacrolimus, but not INH or CNI, can reduce the effects of cyclosporine.
There is no obvious interaction between sirolimus, MMF, or azathioprine.
Short and sweet
Main challenge with Rifampicin that induce Cyto P 450 and decrease therapeutic level of CNI and mTOR
CNI and mTor
Rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin (Tacrolimus, Cyclospirin) and mTOR inhibitor (Sirolimus) should be increased between three- and five-fold.
Cyclosporin:
Clinical practice guidelines from the American Society of Transplantation Infectious Diseases Community of Practice recommend avoiding coadministration of rifampin and cyclosporine if possible; if concomitant use is required a cyclosporine dose increase of 2-fold is recommended.
Ref: 18. Sparkes T, Lemonovich TL, AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants- guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e:13510. [PubMed 30817021]
Prednisolone:
MMF:
RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
Azathioprine: No interaction
Reference:
Uptodate lexicomp drug interaction between Rifampicin, Isoniazid, and Pyrazinamide and the above drugs. Analyzed 27 Feb 23
It is strange to type reference in the middle of a write-up.
You have typed 18th reference. Where are first 17?
Please find below a better version:
Main challenge with Rifampicin that induce Cyto P 450 and decrease therapeutic level of CNI and mTOR
CNI and mTor
Rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin (Tacrolimus, Cyclospirin) and mTOR inhibitor (Sirolimus) should be increased between three- and five-fold.
Cyclosporin:
Clinical practice guidelines from the American Society of Transplantation Infectious Diseases Community of Practice recommend avoiding coadministration of rifampin and cyclosporine if possible; if concomitant use is required a cyclosporine dose increase of 2-fold is recommended. (2)
Prednisolone:
MMF:
RifAMPin may decrease serum concentrations of the active metabolite(s) of Mycophenolate. Specifically, concentrations of mycophenolic acid (MPA) may be decreased.
Azathioprine: No interaction
Reference:
1- Uptodate lexicomp drug interaction between Rifampicin, Isoniazid, and Pyrazinamide and the above drugs. Analyzed 27 Feb 23
2- Sparkes T, Lemonovich TL, AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants- guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e:13510.
Rifampin will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
INH: will increase the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
Rifampin: will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
INH: no significant interaction.
Rifampin: will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
INH: will increase the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism.
INH: no significant interaction.
Rifampin: no significant interaction.
Rifampin: no significant interaction.
INH: no significant interaction. Prednisone.
Reference:
Medscape interaction checker
This is not a good enough reference in a scientific write-up:
Medscape interaction checker
Noted, thanks Prof.
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin :
Isoniazid :
REFERRENCE :
1. Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
2. Antimicrob Agents Chemother. 1980 Nov; 18(5): 661–666. doi: 10.1128/aac.18.5.661
3 .Indian J Crit Care Med. 2021 Jan; 25(1): 67–76.doi: 10.5005/jp-journals-10071-23439
I like your well-referenced though a concise reply..
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
The interaction of the anti-tuberculous drugs (Rifampicin and INH)
Rifampicin: is considered drug inducer.
Tacrolimus: lead to decrease the tacrolimus level as it is considered inducer of CYP3A4.
Cyclosporine: Rifampin, a potent enzyme inducer, has been demonstrated to increase cyclosporine clearance.
Sirolimus: Rifampicin increases the clearance of sirolimus approximately 5.5fold and decreases the maximum concentration (C max ) by 71%
Azathioprine: No significant interaction and might decrease Azathioprine clearance.
Mycophenolate Mofetil: long-term rifampin therapy causes a marked reduction in dose-corrected MPA exposure when administered simultaneously with MMF.
Prednisone: rifampicin increased the plasma clearance of prednisolone by 45%.
INH:
Tacrolimus: The serum concentration of Tacrolimus can be increased when it is combined with Isoniazid.
Cyclosporine: The metabolism of Cyclosporine can be decreased when combined with Isoniazid.
Sirolimus: metabolism of Sirolimus can be decreased when combined with Isoniazid.
Azathioprine: rifampicin increased the plasma clearance of prednisolone by 45%.
Mycophenolate Mofetil: No significant interaction.
Prednisone: serum concentration of Isoniazid can be decreased when it is combined with Prednisone.
References:
The Renal Drug Handbook The Ultimate Prescribing Guide for Renal Practitioners.
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Thanks prof, Sharma.
Holding MMF with active TB is indicated,
Rifampicin, a strong inducer of cytochrome P450 enzyme (CYP3A4, CYP2C19)
Isoniazid – a minor substrate of CYP2E. It moderately inhibits CYP2E1 and may also induce it, while it weakly inhibits CYP3A4.
Rifampicin: Drug information. Up to Date [database on the Internet]. Waltham (MA): UpToDate; 2020[cited 27 Feb 2023] Available from: http://www.uptodate.com.
Isoniazid: Drug information. Up to Date [database on the Internet]. Waltham (MA): UpToDate; 2020[cited 27 Feb 2023] Available from: http://www.uptodate.com.
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Rifampicin, being a hepatic enzyme inducer, its interaction with Tacrolimus leads to sub therapeutic Tac. level and potential allograft rejection. Similarly it reduces cyclosporine and Sirolimus blood level. Rifampicin is increasing metabolism of Azathioprine as well. When given simultaneously, Rifampicin reduced the dose-corrected mycophenolate acid exposure, leading to subtherapeutic drug level. Prednisolone concentration is reduced by 45% owing to increased metabolism.
INH:
Conversely, as an enzyme inhibitor, it increase the level of CNi bioavailability, however no change in metabolism of cyclosporin was reported. INH might increase levelof Sirolimus for the same reason , however , no reports were found to discuss this happening. Azathioprim administration concumitently with INH might be resultant in Hepatitis and pancytopenia. There is no reported interaction with Mycophenolate Mofitel.
INH might increase level and effect of steroid by reducing its metabolism.on the hand steroid may decrease effect of INH by unknown mechanism.
Reference:
1]Dirk R J Kuypers et al. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase.Clin Pharmacol Ther
2005 Jul;78(1):81-8.2] Mously, Alaa et al.Rifampin Drug Interactions with Tacrolimus in Solid Organ Transplant.Transplantation 102():p S602-S603, July 2018.3] K Sud et al. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipientsMethods Find Exp Clin Pharmacol 2000 Oct;22(8):647-9.
I note that there is no reported interaction with MMF. Nonetheless, I would hold off MMF for 6 weeks when treating a transplant recipient for active TB.
Both rifampicin (strong) and INH (weak) are enzyme inducers of cytochrome P450 CYP3A4 and will result in a reduction in the serum level of the following drugs
Hence in kidney transplant patients, it is adviceable to increase the dose of CNIs and mTORs by 3-5 fold of the baseline to avold graft rejection because of low level of the immunosuppressives
Rifampicin affect the matabolization of glucocorticoid, and the recommendation is to double the dose of the steroid to avoid rejection
Antimetabolites, especially azathioprine are know to cause bone marrow suppression and this could be very severe with concomitant use of alopurinol. The bone marrow suppression of antimetabolites will be severe when used together with INH or rifampicin and as a result, azathioprine is usually advised to be withdrawn when the white cell count is less than 3000/mm3 or 50% drop
Azathioprine also cause elevated liver enzymes (ALT, AST )and this could amplify the hepatotoxicity effect of INH (elevated AST, ALT & bilirubinemia) when used together in treatment of PTB
References
Thankyou
Rifampicin
INH
References
1. Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis 2009; 48:1276.
I like your summary
What is the interaction of the anti-tuberculous drugs (Rifampicin and INH) with the following immunosuppression medications?
Rifampicin
====================================================================
Isoniazid
===================================================================
Isoniazid- and rifampicin-induced thrombocytopenia
====================================================================
Reference
Would you effect a reduction in MMF and for how long in light of the effect of INH on mycophenolic acid?
Typing whole sentence in bold or typing in capitals amounts to shouting.
Would you effect a reduction in MMF and for how long in light of the effect of INH on mycophenolic acid?
Thank you Prof. Sharma
very sorry
I searched many sites, but I did not get any information except for what I wrote.
Drug Interactions;
–Rifamycins;
-Have an induction effect on different drug metabolizing enzyme systems, most notably the cytochrome P450 (CYP) 3A4, which lead to a reduction in the blood levels of most immunosuppressive drugs used after SOT (tacrolimus, cyclosporine, sirolimus, everolimus, and even corticosteroids).
-A lower blood level of these drugs is associated with higher risk of graft rejection.
-Therefore, close monitoring and continuous dose adjustment are highly recommended.
–Rifampin has the most potent enzyme induction effect.
-2-5-fold increments in the daily dose of cyclosporine, tacrolimus, and mammalian target of rapamycin inhibitors are generally necessary to maintain trough levels of the drug in the therapeutic range.
-Although enzyme induction start within hours after the first dose of rifampin, maximum effect is reached in about 1 to 2 weeks and slowly declines over 2 weeks after stopping its use.
-Thus, therapeutic drug monitoring of immunosuppressive drugs should be more frequent in the beginning of rifampin treatment and in the first 2 weeks after its interruption.
-Despite these drug interactions, rifampicin is not contraindicated in SOT recipients.
–Rifabutin, a rifamycin with weaker and more limited spectrum of enzyme induction, is an alternative for rifampin.
-It has been demonstrated to be as effective as rifampin for the treatment of TB in trials conducted in nontransplant patients.
-Its weaker effect on CYP3A4 makes it easier to maintain therapeutic blood levels of calcineurin and mammalian target of rapamycin inhibitors during TB treatment.
-Isoniazid (INH);
-Has a potential effect to cause hepatotoxicity and cytopenia, so; it can interact with Azathioprine or MMF to augment their side effects.
–Hepatotoxicity is a serious dose limiting side effects of both Isoniazid and Rifampicin and this risk is further accentuated in patients with pre-existing liver disease and alcoholics.
-Peripheral neuropathy caused by Isoniazid can be prevented by co-administration of pyridoxine.
-References;
-Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis. 2005;40: 581–587.
-Singh N, Paterson DL. Mycobacterium tuberculosis infection in solidorgan transplant recipients: impact and implications for management. Clin Infect Dis. 1998;27:1266–1277.
-Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet. 2003;42:819–50.
-Sun HY, Munoz P, Torre-Cisneros J, et al. Tuberculosis in solid-organ transplant recipients: disease characteristics and outcomes in the current era. Prog Transplant. 2014;24:37–43.
-Crabol Y, Catherinot E, Veziris N, et al. Rifabutin: where do we stand in 2016? J Antimicrob Chemother. 2016;71:1759–71.
-Hickey MD, Quan DJ, Chin-Hong PV, et al. Use of rifabutin for the treatment of a latent tuberculosis infection in a patient after solid organ transplantation. Liver Transpl. 2013;19:457–61.
–Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
Would you effect a reduction in MMF and for how long in light of the effect of INH on mycophenolic acid?
Thanks;our Prof. Sorry;
Icouldnt find significant interaction between INH and Mycophenolic acid.
DRUGS DECREASING TACROLIMUS CONCENTRATION (CYTOCHROME P-450 3A4 INDUCERS)
Rifabutin/rifampicin, isoniazid
The recommended course of action is to raise the dosage of calcineurin inhibitor or rapamycin by a factor of three to five, while closely monitoring the amounts of the drug in the blood. Rifampin induction of CYP3A4 takes several days to take effect, often reaches its peak within a week, and continues for a few days to several weeks.
Rifabutin has comparable action against M. tuberculosis but poorer cytochrome p450 induction.
Combining isoniazid, rifampin, and pyrazinamide increases hepatotoxicity, especially in liver recipients. Watch the liver function testing. Isoniazid may cause neurotoxicity and peripheral neuropathy.
Typing whole sentence in capitals or in bold amounts to shouting.
·Tacrolimus
Examples of P-glycoprotein inducers:
Examples of P-glycoprotein inhibitors:
Examples of P-glycoprotein substrates:
Drugs that interact with tacrolimus through CYP3A enzymes
Inhibitors include:
Substrates:
Inducers:
Reference
A Nemanja K. Rančić, Neven N. Vavić, Aleksandra M. Kovačević, Momir M. Mikov, Viktorija M. Dragojević – Simić, Drug-drug interactions of tacrolimus, Hospital Pharmacology. 2015; 2(3):291-296 UDC: 615.37.015.4
==========================
·Cyclosporine
Drugs that increase cyclosporine plasma concentrations include:
Drugs that lower cyclosporine plasma concentrations include:
Drugs that may increase the risk of cyclosporine -associated nephrotoxicity:
Cyclosporin itself may significantly affect the pharmacokinetics &/or pharmacodynamics of co-administered drugs, such as:
References
Maria Delia Colombo, Renata Perego and Gilberto Bellia,
Drug Interactions and Potential Side Effects of Cyclosporine, In: Advances in Medicine and Biology. Volume 74 ISBN: 978-1-62948-379-5 Editor: Leon V. Berhardt © 2014 Nova Science Publishers, Inc.
==========================
·Sirolimus
References
Rapamune® (sirolimus) Oral Solution and Tablets NDA 21-083/S-030 NDA 21-110/S-038 Page 3
==========================
·Azathioprine
Use with xanthine oxidase (XO) inhibitors (allopurinol, febuxostat):
Use with Aminosalicylates(sulphasalazine, mesalazine, or olsalazine):
Use with Other Agents Affecting Myelopoesis (e.g., co-trimoxazole):
Use with ACE inhibitors:
Use with Warfarin:
Use with ribavirin:
References
IMURAN ® (azathioprine) 50-mg Scored Tablets PRODUCT INFORMATION
==========================
·Mycophenolate Mofetil
Use with anti-bacterial agents
Metronidazole:
Amoxicillin/ clavulanate:
Ciprofloxacin:
Levofloxacin:
Anti-tubercular agents
Rifampin:
Antifungal agents
Isavuconazole:
References
CellCept® (mycophenolate mofetil capsules) (mycophenolate mofetil tablets) Drug Information
==========================
Prednisone
Azole antifungal agents:
Isavuconazole:
Anti-tubercular agents
Rifampin:
INH:
Antiviral agents (ritonavir):
References
Edward T Van Matre, Gowri Satyanarayana, Robert L. Page II, and Marilyn E. Levi, Pharmacokinetic Drug–Drug Interactions Between Immunosuppressant and Anti-Infective Agents: Antimetabolites and Corticosteroids, January 2018 Annals of transplantation: quarterly of the Polish Transplantation Society 23:66-74 DOI:10.12659/AOT .906164
Hi Dr Mohamed,
I like your very detailed summary,
I quote your response:
Amoxicillin/ clavulanate: Reduced MPA exposure requires a 25% increase in MMF dosage.
Does it mean that you would increase the dose of MMF when a transplant recipient needs amoxycillin?
Thank you, dear Prof. Ajay
Honestly, I am not sure.
Though, I don’t think it would be necessary to do so, except if there is a compelling indication for the use of this antibiotic (guided by sensitivity results) for a prolonged duration.
Due to strong interactions between this type of medication and the calcineurin inhibitors and rapamycin, rifampin should be used with caution (sirolimus). Tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus serum concentrations are decreased by the rifamycins (particularly rifampin) through stimulation of the cytochrome p450 isoenzyme CYP3A4, and taking a rifamycin together with these medications has been linked to the emergence of rejection.
Rifamycins also reduce levels of glucocorticoids, although this has been less well characterized
If rifampin is used Increase dose of calcineurin inhibitor or rapamycin, monitor serum concentrations.
Streptomycin is generally avoided in SOT recipients due to risk of nephrotoxicity
Azathioprine and Mycophenolate Mofetil – No interactions found
Short and sweet
Effect of INH & Rifampicin other immune suppression:
Rifampicin is a strong inducer of the cytochrome P450 CYP3A enzyme and together with INH may lead to decrease levels of the following drugs:
However, INH may decrease the excretion rate of Mycophenolic acid which could result in a higher serum level.
Rifampacin & INH may also affect the metabolism of glucocorticoids leading to decrease levels of ;
Source, M.tuberculosis infection in renal transplant by Bogdan et al., Drug.com encyclopedia
Would you effect a reduction in MMF and for how long in light of the effect of INH on mycophenolic acid?
Thnxs prof,
. The effect may not be very significant
Rifampicin:
Rifampicin will decrease level and affect of tacrolimus/ Prednisolone/ Sirolimus by affecting hepatic and intestinal enzymes cyp3A4; (So need to be avoided rifampicin with these drugs or use alternative therapy.
Cyclosporine need modification of dose because Rifampicin will decrease level and affect by affecting hepatic and intestinal enzymes cyp3A4.
No dose adjustment of MMF and azathioprine with rifampicin.
Isoniazid:
Prednisone decrease effect of INH by unknown mechanism.
Isoniazid will decrease level and affect of Sirolimus by affecting hepatic and intestinal enzymes cyp3A4; So should be avoided or use alternative therapy.
Isoniazid with tacrolimus should be use with caution and monitoring because Isoniazid will decrease level and affect of tacrolimus.
No dose adjustment with cyclosporine and azathioprine or MMF.
Reference from medscape. com
Thanks, Sahar
Are you sure about the drug interaction of INH?
Tacrolimus – rifampin will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. isoniazid will increase the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
Cyclosporine – rifampin will decrease the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. rifampin will decrease the level or effect of cyclosporine by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely.
Sirolimus – rifampin will decrease the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Rifampin will decrease the level or effect of sirolimus by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
Isoniazid will increase the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
Azathioprine – No interactions found
Mycophenolate Mofetil – No interactions found
Prednisone – Rifampin will decrease the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Rifampin will decrease the level or effect of prednisone by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
Isoniazid will increase the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
Reference – Medscape
Thanks, Filipe
Are you sure about the drug interaction of INH?
Professor, I used Medscape for orientation.
https://reference.medscape.com/drug-interactionchecker
Close monitoring is the most important, but there will be interactions.
I note that interactions with cytochrome enzymes affect INH induced . INH-induced liver injury.
The rifamycins, particularly rifampin, reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of the cytochrome p450 isoenzyme CYP3A4.
The combination of rifampin with members of this class of drugs can lead to the development of rejection unless dose adjustments and therapeutic drug monitoring are performed carefully.
Rifabutin is an attractive alternative to rifampin because it is a weaker inducer of cytochrome p450. However, there is less experience with rifabutin in the treatment of TB.
Similarly, the long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout. Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by the simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.
References:
· Tuberculosis in solid organ transplant candidates and recipients – UpToDate
· Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther. 2005 Jul;78(1):81-8. doi: 10.1016/j.clpt.2005.03.004. PMID: 16003296.
Thanks, Fakhriya for addressing the effect of INH on MPA. This is something I have learned today. Do not forget its additive effect on the WBCs.
1- rifampicin RFM is a strong cytochrome (CY) P3A4 inducer.
2- it significantly reduce blood levels of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi), steroids and even mycophenolate mofetil (MMF) by inducing CYP3A4-mediated immunosuppressant metabolism.
3- to minimize the effect of this drug-to-drug interaction without compromising efficacy against TB, one recommendation is to use rifabutin RFB instead of RFM. RFB is structurally similar to RFM, has the same potency against TB and has almost the same mechanism of interaction with immunosuppressants. Although, in contrast to RFM, RFB is a weak CYP3A4 inducer and therefore, may not significantly reduce immunosuppressant trough levels.
Yu-Chen Wang , Noruel Gerard Salvador, Chih-Che Lin , Chao-Chien Wu , Ting-Lung Lin , Wei-Feng Lee , Yi-Chia Chan , Chao-Long Chen , Jeffrey Samuel Co , Domelle Dave Encarnacion. Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. Biomedical Journal. Volume 44, Issue 6, Supplement 2, December 2021, Pages S162-S170
as regard INH it is safe and can be used with CNI without any change in their bioavailability
K Sud , T Muthukumar, B Singh, S K Garg, H S Kohli, V Jha, K L Gupta, V Sakhuja. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients.
Methods Find Exp Clin Pharmacol. 2000 Oct;22(8):647-9.
Thanks, Riham
What is the effect of INH in patients on antiproliferative (azathioprine and MMF)?
it is used safe
no drug-drug interaction found between both of them
Rifampicin is a potent enzyme inducer. Therefore, its use is associated with a severe drops in the serum levels of Cyclosporine, Tacrolimus, everolimus and Sirolimus due to the induction of the CYP3A enzyme (1).
Isoniazid (INH) has a potential effect to cause hepatotoxicity and cytopenia, so, theoretically, it can interact with Azathioprine or MMF to augment their side effects, as illustrated in the attached table (2).
I could not find a direct interaction between prednisone and Rifampicin or Isoniazid (INH).
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
2) Subramanian AK, Morris MI, AST Infectious Diseases Community of Practice. Mycobacterium tuberculosis infections in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:68-76.
Thanks, Ahmed for the excellent answer
Tacrolimus
rifampicin decrease the plasma levels
INH will increase the levels
Cyclosporine
rifampicin decrease the plasma levels
Sirolimus
rifampicin decrease the plasma levels
INH will increase the plasma levels
Azathioprine
No interaction
Mycophenolate Mofetil
Mycophenolate is metabolized into mycophenolic acid, which undergoes glucuronidation by uridine diphosphate glucuronosyltransferases in the liver, kidney, and intestine to its inactive metabolite (7-O-glucuronide). Rifampicin induces intestinal, kidney, and liver glucuronidation of mycophenolic acid by UGTs and reduces enterohepatic recirculation and absorption of mycophenolic acid. Also one metabolite of MMF, acyl-glucuronide, gets accumulated and attains higher blood level in presence of rifampicin, which may increase the toxicity or adverse effects. Hence in presence of rifampicin, its plasma level should be monitored, and the dose should be adjusted accordingly
Prednisone
Rifampicin is a potent liver enzyme inducer, which increases the metabolism of the steroids, thereby reducing the effect of steroids by blood levels. Steroid dose should be increased initially, and should be gradually decreased, once rifampicin is discontinued.
INH will increase the level