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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2011  |  Volume : 22  |  Issue : 1  |  Page : 112-115
Drug interaction between rifampicin and sirolimus in transplant patients


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

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Date of Web Publication30-Dec-2010
 

   Abstract 

We report two cases of drug interaction between rifampicin and sirolimus in renal trans≠plant patients who were diagnosed with tuberculosis after transplantation and induction of immuno≠suppressive therapy with sirolimus. The dosage of sirolimus had to be increased, in one case up to six-fold and in the second case up to five-fold, to maintain serum levels after starting the rifampicin. The two patients tolerated the treatment well, with no signs of tuberculosis and good renal function.

How to cite this article:
Ngo B T, Pascoe M, Kahn D. Drug interaction between rifampicin and sirolimus in transplant patients. Saudi J Kidney Dis Transpl 2011;22:112-5

How to cite this URL:
Ngo B T, Pascoe M, Kahn D. Drug interaction between rifampicin and sirolimus in transplant patients. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Jul 22];22:112-5. Available from: http://www.sjkdt.org/text.asp?2011/22/1/112/74378

   Introduction Top


In solid organ transplantation, patients usually require life-long immunosuppressive agents. These patients often receive additional medica≠tions to prevent or treat infectious complica≠tions. An example of such a life-threatening complication is infection with Mycobacterium tuberculosis. The interaction between the immu≠nosuppressive agents and the anti-tuberculosis drugs could have significant consequences. [1],[2],[3],[4] In this paper, we present two clinical cases of drug interaction between rifampicin and sirolimus.


   Case Reports Top


Case 1

A 60-year-old man with a long-term history of hypertension and chronic glomerulonephritis for 20 years began hemodialysis early, in 1992, and received his first cadaveric kidney in June 1992. He lost the transplant after a few months because of primary non-function and a graft nephrectomy was performed. He received a se≠cond cadaveric kidney in May 1993 with imme≠diate graft function. He subsequently developed steroid-induced diabetes. The graft function deteriorated because of chronic rejection and the patient received a third transplant in August 2000.

In April 2003, the patient was enrolled in a sirolimus clinical trial and was started on a loading dose of 20 mg followed by a mainte≠nance dose of 8 mg per day. He tolerated the treatment well without any complaints and had a good graft function. The dose of sirolimus was decreased to 4 mg per day based on the sirolimus levels. The patient presented after se≠veral months with complaints of intermittent chest pain. Although the chest was clinically clear, the chest radiograph showed a right upper lobe peripheral lesion with a rounded specu≠lated appearance and pleural reaction. There was no hilar adenopathy. A computed tomographic scan of the chest showed an irregular soft tissue mass with air bronchograms in the anterior seg≠ment of the right upper lobe. Mycobacterium tuberculosis was eventually diagnosed by in≠duced sputum, which was positive for acid-fast bacilli. The patient was started on treatment with a combination of rifampicin, isoniazid, pyrazi≠namide and ethambutol. The dose of sirolimus was increased immediately to 30 mg per day to maintain the target levels [Table 1]. Serum levels remained above 10 ng/mL. On follow-up, the patient did well, with no signs of TB and good renal function.
Table 1: Sirolimus levels before and after starting rifampicin.

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Case 2

A 28-year-old man suffered from reflux neph≠ropathy that was diagnosed at the age of 2 years, and for which he underwent a right-sided nephrectomy, began dialysis in 1996 and re≠ceived two cadaveric transplants later. Both these transplants were lost because of chronic graft rejection. He received his third transplant in July 2002 and had immediate graft function.

In May 2003, the patient was enrolled in a sirolimus clinical trial. He received a maintenance dose of sirolimus of 4-6 mg per day, with levels maintained over 10 ng/mL. In August 2004, he presented with a cough, pyrexia and feeling ge≠nerally unwell. On clinical examination, crackles could be heard on the right side of his chest. The chest radiograph revealed a lung opacity and a diagnosis of pulmonary TB was made by finding acid-fast bacilli in the sputum. He was started on anti-TB treatment, which included ri≠fampicin. The serum level of sirolimus decreased from 12 ng/mL to 5.2 ng/mL after treatment with rifampicin [Table 1]. The sirolimus dosage was increased five-fold to 25 mg daily to maintain adequate serum levels. The patient did well with that regimen and showed no signs of TB, graft dysfunction or rejection.


   Discussion Top


The cytochrome P450 (CYP) enzyme system is responsible for most biotransformations of endogenous and exogenous substances. The most prominent of the genes expressing CYP is the CYP3A gene family, encoding cytochromes P4503A (CYP3As), which constitute 30% and 70% of the total CYPs in most human livers and intestines, respectively. [5],[6] CYP3As catalyze up to 70% of the oxidation reactions of clinically important drugs. [5],[6],[7]

CYP3A is essential for the metabolism of se≠veral immunosuppressive agents. CYP3A is res≠ponsible for up to 90% of cyclosporine, tacro≠limus and sirolimus metabolism. [8] The potential for clinically significant drug interactions can lead to severe complications, such as over im≠munosuppression and toxicity or under-immu≠nosuppression and rejection. Genetic variations and environmental factors also influence the CYP3A concentrations and, thus, immunosup≠pressive drug metabolism is expected to vary among recipients. [5],[8]

Sirolimus has been used for prophylaxis against rejection in patients receiving renal, heart, liver, lung and kidney-pancreas transplants as a part of the multidrug immunosuppressive regimen. It is poorly absorbed, with a reported bioavaila≠bility of 15%, [9],[10] and it is extensively metabo≠lized by o-demethylation and/or hydroxylation. [9],[11]

The elimination of sirolimus is primarily hepa≠tic, with some intestinal metabolism by the CYP3A4 isoenzyme in the intestinal wall and liver. [10],[12],[13] Sirolimus is a substrate for both CYP3A4 and P-glycoprotein (P-gp) because P≠gp and CYP3A4 are often co-expressed in the tissues. [12],[13]

The expression of CYP3A protein and mRNA is highly inducible after treatment with many agents. Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase the siro≠limus levels. Alternatively, inducers of CYP≠3A4 may increase the metabolism of sirolimus and decrease the sirolimus levels. Co-adminis≠tration of sirolimus with strong inhibitors of CYP3A4, such as imidazole and triazole anti≠fungals, calcium channel blockers and macro≠lide antimicrobials, or inducers of CYP3A4, such as antiepileptic drugs and anti-TB agents like rifampicin, could have serious consequen≠ ces. [9],[11],[14]

Rifampicin is known to induce hepatic enzymes such as the CYP2C8, leading to reduced levels of various immunosuppressive drugs, including cyclosporine and steroids. [2],[3],[8] Because rifampicin is a strong inducer of CYP3A4, it increases the clearance of sirolimus approximately 5.5≠fold and decreases the maximum concentration (C max ) by 71%. [9],[11] The risk of graft rejection is increased if the serum level of sirolimus is not adjusted carefully. Singh and Paterson reported a 30% incidence of graft rejection and a 20% incidence of graft loss in such patients. [15] There was a significant variation among individuals in the expression of hepatic CYP3A proteins as well as in the clearance of many CYP3A-meta≠bolized drugs. [5],[6] Burman and colleagues repor≠ted a 10-fold variation among individuals in the extent to which rifampicin could induce CYP≠3A4 expression in humans. [7] Rifampacin has major effects on drug efficacy, toxicity and the≠rapeutic outcome.

Our two renal transplant recipients had to increase the dose of sirolimus after starting anti≠TB treatment with rifampicin 5.5-6-folds to maintain adequate trough levels. It has been pro≠posed that rifampicin increases the clearance of sirolimus by approximately 5.5-fold. [9],[11]

In conclusion, in transplant patients in whom strong inhibitors or inducers of CYP3A4 are in≠ dicated, alternative therapeutic agents with a lower potential for inhibition or induction of CYP3A4 should be considered or blood levels of the drugs should be monitored carefully so that the drug interaction does not significantly jeopardize the renal allograft function and patient survival.

 
   References Top

1.Rubin RH. Infectious disease complications of renal transplantation. Kidney Int 1993;44:221.  Back to cited text no. 1
[PUBMED]    
2.Higgins RM, Cahn AP, Porter D, et al. Myco≠bacterial infections after renal transplantation. Q J Med 1991;78:145.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Buffington GA, Dominguez JH, Piering WF, Hebert LA, Kauffman HM Jr, Lemann J Jr. Interaction of rifampin and glucocorticoids. Ad≠verse effect on renal allograft function. JAMA 1976;236:1958.  Back to cited text no. 3
[PUBMED]    
4.Peschke B, Ernst W, Gossmann J, Kachel HG, Schoeppe W, Scheuermann EH. Antituberculous drugs in kidney transplant recipients treated with cyclosporine. Transplantation 1993;56:236.  Back to cited text no. 4
[PUBMED]    
5.Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998;35:361.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Watkins PB. Role of cytochromes P450 in drug metabolism and hepatotoxicity. Semin Liver Dis 1990;10:235.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Burman WJ, Gallicano K, Peloquin C. Compa≠rative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmaco≠kinet 2001;40:327.  Back to cited text no. 7
    
8.Holt CD. Drug interactions with immunosup≠ pressive agents. Transplant Trends 2004;6:4.  Back to cited text no. 8
    
9.Physicians' Desk Reference, 58 th ed. Montvale, NJ: Medical Economics Company; 2004.  Back to cited text no. 9
    
10.Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Phar≠macol 1997;37:405.  Back to cited text no. 10
    
11.Sehgal SN. Rapamune (Sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit 1995;17:660.  Back to cited text no. 11
[PUBMED]    
12.Yatscoff RW, Aspeslet LJ. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther Drug Monit 1998;20:459.  Back to cited text no. 12
[PUBMED]  [FULLTEXT]  
13.Sattler M, Guengerich FP, Yun CH, Christians U, Sewing KF. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 1992;20:753.  Back to cited text no. 13
[PUBMED]  [FULLTEXT]  
14.Kovarik JM, Hartmann S, Figueiredo J, Rouilly M, Port A, Rordorf C. Effect of rifampin on ap≠parent clearance of everolimus. Ann Pharma≠ cother 2002;36:981.  Back to cited text no. 14
    
15.Singh N, Paterson DL. Mycobacterium tuber≠culosis infection in solid-organ transplant reci≠pients: impact and implications for management. Clin Infect Dis 1998;27:1266.  Back to cited text no. 15
[PUBMED]  [FULLTEXT]  

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Correspondence Address:
Delawir Kahn
Department of Surgery, Medical School Observatory, 7925, Cape Town
South Africa
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PMID: 21196624

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    Tables

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