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Immunosuppressant Drug Interactions

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Presentation on theme: "Immunosuppressant Drug Interactions"— Presentation transcript:

1 Immunosuppressant Drug Interactions
A comparison of sirolimus and tacrolimus My Dung Dang September 2008 For GeneMedRx by Genelex

2 Transplant Rejection Transplant of organ introduces foreign tissue to the body The body’s immune system sees this foreign tissue, thinks it’s bad and start producing lymphokines including IL-2 The lymphokines then activates the immune system even further, leading to a vicious cycle of foreign tissue destruction rejection

3 Tacrolimus (PROGRAF) Class: macrolide immunosuppressant, calcineurin inhibitor (CNI), which includes cyclosporin MOA: inhibits the activation of T-lymphocytes and the formation of IL-2 Narrow therapeutic window Levels too high: toxicities (i.e. nephrotoxicity, mental confusion, hyperglycemia and hypertension) Levels too low: transplant rejection

4 Sirolimus (RAPAMUNE) Class: macrolide immunosuppressant, mTOR inhibitor MOA: inhibits immune cell growth and decreasing IL-2 activities Narrow therapeutic window Levels too high: toxicities (i.e. mental confusion, nephrotoxicity) Levels too low: transplant rejection Mamalian Target of Rapamycin

5 Figure 2 Mechanisms of action of maintenance immunosuppressive agents
Samaniego M et al. Drug Insight: maintenance immunosuppression in kidney transplant recipients. Nat Clin Pract Neprol 2006;2: 688–699 doi: /ncpneph0343

6 Metabolism Pathways Tacrolimus Sirolimus Substrate CYP3A4 CYP3A5
CYP2D6 CYP2E1 CYP2A6 UGT2B7 P-gp CYP3A4 - intestinal Inhibitor CYP3A4 (moderate) UGT1A1 Inducer NONE

7 Drugs that Increase the Level of Immunosuppressants
Drug name Metabolism route Tacrolimus Sirolimus Chloramphenicol Unknown (possibly UGT) Clotrimazole CYP3A4, possibly P-gp CYP3A4 Mibefradil (withdrawn) CYP3A4, CYP2D6 Danazol, Cimetidine, Metoclopramide, Bromocriptine, Protease inhibitors, Nicardipine, Cisapride CYP3A4 and/or P-gp Felodipine, Lansoprazole, Levofloxacin, Nefazodone, Pomelo juice, Methylprednisolone

8 Drugs that Increase the Level of Immunosuppressants (con’t)
Drug name Metabolism route Tacrolimus Sirolimus Quinidine P-gp Metronidazole, Nifedipine CYP3A4, CYP3A5 Omeprazole Conflicting data with CYP3A4 (↕) Ergotamine, Ethinyl estradiol, Josamycin, Miconazole, Midazolam, Tamoxifen CYP3A (in-vitro, in-vivo data not available) Diltiazem, Verapamil, Grapefruit juice, Cyclosporin, Azole-antifungals, Macrolide antibiotics CYP3A4, P-gp

9 Drugs that Decrease the Level of Immunosuppressants
Drug name Metabolism route Tacrolimus Sirolimus Corticosteroids, Rifampin, St. John’s Wort CYP3A4, P-gp Phenytoin, Phenobarbital, Carbamazepine, CYP3A4 Rifapentin

10 Drugs that are Increased by the Immunosuppressants
Drug name Metabolism route Tacrolimus Sirolimus Irinotecan UGT1A1 Rifampin CYP3A4, P-gp Simvastatin CYP3A4 Cerivastatin (withdrawn) Probably through CYP3A4 Erythromycin, S-(-) Verapamil CYP3A4, CYP3A5, P-gp

11 Drugs that Lack Interaction with the Immunosuppressants
Drug name Metabolism route Tacrolimus Sirolimus Methotrexate, Micafungin, Pantoprazole, Sirolimus x Acyclovir, Atorvastatin, Digoxin, Ethinyl estradiol/ Norgestrel, Glyburide, Nifedipine, Tacrolimus, Prednisolone, BACTRIM X MMF Conflicting data with CYP3A5, UGT Rabeprazole Conflicting data with CYP2C19 PMs Sildenafil Somewhat conflicting data, same substrate of CYP3A4

12 GeneMedRX A drug interaction database from Genelex, a DNA testing company Advantages: Maintained by healthcare professionals Interactions provides a summary of the literature Provides link to PubMed articles referenced Disadvantage: Not FDA approved

13 PubMed Search for Clerkship Project
Search terms # of articles available through the University of Washington # of articles added to the Editor “tacrolimus interaction” 764 32 full texts 10 abstracts “sirolimus interaction” 478

14 Notes

15 Notes

16 GeneMedRx is Growing!!!

17 Why the immunosuppressants?
The two drugs of focus have narrow therapeutic windows and have many potential interaction due to their metabolism pathways. It is important for me to know more about these interactions as a pharmacist to help my patients from getting toxicities or unnecessary rejections that could be prevented.

18 Special Thanks to Dr. Oesterheld, Dr
Special Thanks to Dr. Oesterheld, Dr. Patterson, Kristine Ashcraft and Howard Coleman with the Staff at Genelex

19 References Cutler C, Stevenson K, Kim H, Richardson P, Ho V, Linden E ,et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood Sep 5 [cited 2008 Sep 11]. Available from: Harzallah K, Abderrahim E, Chareffedine K, Yeich S, Belhadj R, Skhiri H, et al. Cancers after renal transplantation: multicenter experience. Saudi J Kidney Dis Transpl. 2008;19(5): Hamalainen M, Korhonen R, Moilanen E. Calcineurin inhibitors down-regulate iNOS expression by destabilizing mRNA. Int Immunopharmacol [cited 2008 Sep 9]. Available from: Lam S, Partovi N, Ting L, Ensom M. Corticosteroid interactions with cyclosporin, tacrolimus, mycophenolate, and sirolimus: fact or fiction? Ann Pharmacother Jul/Aug;42; Loh P, Lou H, Zhao Y, Chin Y, Vathsala A. Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. Trans Proceed. 2008;40: Surowiec D, DePestel D, Carver P. Concurrent administration of sirolimus and voriconazole: a pilot study sssessing safety and approaches to appropriate management. Pharmacotherapy. 2008;28(6): Thervet E, Anglicheau D, Legendre C, Beaune P. Role of pharmacogenetics of immunosuppressive drugs in organ transplantation. Ther Drug Monit Apr;30(2): Groetzner J, Kaczmarek I, Wittwer T, Strauch J, Meiser B, Wahlers T, et al. Caspofungin as first-line therapy for the treatment of invasive aspergillosis after thoracic organ transplantation. J Hea Lun Jan;27(1):1-6. Op den Buijsch R, Christiaans M, Stolk L, Vries J, Cheung C, Undre N, et al. Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol. 2007;21: Miura M, Inoue K, Kagaya H, Satoh S, Tada H, Sagae Y, et al. Influence of rabeprazole and Lansoprazole on the Pharmacokinetics of Tacrolimus in Relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipients. Biopharm Drug Dispos. 2007;28: Roedler R, Nauhauser M, Penzak S. Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? Ann Pharmacother Apr;41: Picard N, Djebli N, Sauvage F, Marquet P. Metabolism of sirolimus in the presence or absence of cyclosporine by genotyped human liver microsomes and recombinant cytochromes P450 3A4 and 3A5. Drug Metab Dispos. 2007;35(3):

20 References Saad A, Depestel D, Carver P. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy. 2006;26(12): Falger JC, Mueller T, Arbeiter K, Boehm M, Regele H, Balzar E. Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. Pediatr Transplant. 2006;10: Marty F, Lowry C, Cutler C, Campbell B, Fiumara K, Baden L, et al. Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12: Saitoh H, Saikachi Y, Kobayashi M, Yamaguchi M, Oda M, Yuhki Y, et al. Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine. Eur J Pharm Sci Feb 2;28:34-42. Guaraldi G, Cocchi S, Codeluppi M, Di Benedetto F, Bonora S, Pecorari M, et al. Role of therapeutic drug monitoring in a patient with human immunodeficiency virus infection and end-stage liver disease undergoing orthotopic liver transplantation. Trans Proceed. 2005;37: Mori T, Aisa Y, Nakazato T, Yamazaki R, Ikeda Y, Okamoto S. Tacrolimus-azithromycin interaction in a recipient of allogeneic bone marrow transplantation. Transpl Int. 2005;18: Fireman M, DiMartini A, Armstrong S, Cozza K. Med-psych drug-drug interactions update: immunosuppressants. Psychosomatics Jul/Aug;45: Anglicheau D, Flamant M, Schlageter M, Marinez F, Cassinat B, Beaune P, et al. Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation. Nephrol Dial Transplant. 2003;18:2409–2414. Armstrong S, Cozza K, Pimentel E. Med-psych drug-drug interactions update: immunosuppressants. Psychosomatics Sep/Oct;43: Cvetkovic R, Goa K. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8): Kotanko P, Kirisits W, Skrabal F. Rhabdomyolysis and acute renal graft impairment in a patient treated with simvastatin, tacrolimus, and fusidic acid. Nephron. 2002;90:234–235. Takahashi K, Yano I, Fukuhara Y, Katsura T, Takahashi T, Ito N, et al. Distinct effects of omeprazole and rabeprazole on the tacrolimus blood concentration in a kidney transplant recipient. Drug Metab Pharmacokinet. 2007;22(6): Available from:

21 References Shimoeda S, Ohta S, Kobayashi H, Saitou H, Kubota A, Yamato S, et al. Analysis of the blood level of micafungin involving patients with hematological diseases: new findings regarding combination therapy with tacrolimus. Biol Pharm Bull. 2005;28(3): Hebert M, Blough D, Townsend R, Allison M, Buell D, Keirns J, et al. Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol. 2005;45: Available from: Ikeda F, Tanaka S, Ohki H, Matsumoto S, Maki K, Katashima M, et al. Role of micafungin in the antifungal armamentarium. Curr Med Chem. 2007;14: Dowell J, Stogniew M, Krause D, Henkel T, Damle B. Lack of pharmacokinetic interaction between anidulafungin and tacrolimus. J Clin Pharmacol. 2007;47: Available from: Zimmerman J. Exposure-response relationships and drug interactions of sirolimus. AAPS J. 2004;6(4):1-12. Baciewicz A, Chrisman C, Finch C, Self T. Update on rifampin and rifabutin drug interactions. Am J Med Sci Feb;335(2): Kane G, Lipsky J. Drug-grapefruit juice interactions. Mayo Clin Proc Sep;75(9): Smith HE, Jones JP 3rd, Kalhorn TF, Farin FM, Stapleton PL, Davis CL, et al. Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease. Pharmacogenet Genomics. Epub 2008 Aug 30. PMID: Golshayan D, Pascual M. Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation. Transpl Immunol. Epub 2008 Sep 2. PMID: Filler G, Bendrick-Peart J, Strom T, Zhang YL, Johnson G, Christians U, et al. Characterization of sirolimus metabolites in pediatric solid organ transplant recipients. Pediatr Transplant. Epub 2008 May 11. PMID: Anglicheau D, Legendre C, Beaune P, Thervet E. Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics Jul;8(7): Kuypers DR, de Jonge H, Naesens M, Vanrenterghem Y. Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients. Pharmacogenet Genomics. Epub 2008 Aug 13. PMID:

22 References Gobernado M, Cantón E. [Anidulafungin]. Article in Spanish. Rev Esp Quimioter Jun;21(2): PMID: Catalán González M, Montejo González JC. [Anidulafungin: a new therapeutic approach in antifungal therapy. Pharmacology of anidulafungin]. Article in Spanish. Rev Iberoam Micol Jun;25(2): PMID: Renders L, Czock D, Schöcklmann H, Kunzendorf U. Determination of the pharmacokinetics of cerivastatin when administered in combination with sirolimus and cyclosporin A in patients with kidney transplant, and review of the relevant literature. Int J Clin Pharmacol Ther Nov;41(11): Teicher E, Vincent I, Bonhomme-Faivre L, Abbara C, Barrail A, Boissonnas A, et al. Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study. Clin Pharmacokinet. 2007;46(11): Ricciardi S, Van Wanzeele F, Troisi R. Infections and immunosuppression as specific problems in a HIV + patient transplanted for end-stage alcoholic cirrhosis. Acta Chir Belg Mar-Apr;107(2):215-8. Hosohata K, Masuda S, Ogura Y, Oike F, Takada Y, Katsura T, et al. Interaction between tacrolimus and lansoprazole, but not rabeprazole in living-donor liver transplant patients with defects of CYP2C19 and CYP3A5. Drug Metab Pharmacokinet. 2008;23(2):134–138. Sirolimus product insert. Wyeth Pharmaceutical Inc. Revised January Available from: Tacrolimus product insert. Astellas Pharma US, Inc. Revised April Available from:

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