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

My Dung DangSeptember 2008

For GeneMedRx by Genelex

A comparison of sirolimus and tacrolimus

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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

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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 windowLevels too high: toxicities (i.e. nephrotoxicity,

mental confusion, hyperglycemia and hypertension)

Levels too low: transplant rejection3

Sirolimus (RAPAMUNE) Class: macrolide immunosuppressant,

mTOR inhibitor

MOA: inhibits immune cell growth and decreasing IL-2 activities

Narrow therapeutic windowLevels too high: toxicities (i.e. mental

confusion, nephrotoxicity)Levels too low: transplant rejection

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Samaniego M et al. Drug Insight: maintenance immunosuppression in kidney transplant recipients. Nat Clin Pract Neprol 2006;2: 688–699 doi:10.1038/ncpneph0343

Figure 2 Mechanisms of action of maintenance immunosuppressive agents

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Metabolism Pathways

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Drugs that Increase the Level of Immunosuppressants

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Drugs that Increase the Level of Immunosuppressants (con’t)

Drugs that Decrease the Level of Immunosuppressants

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Drugs that are Increased by the Immunosuppressants

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Drugs that Lack Interaction with the Immunosuppressants

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GeneMedRX A drug interaction database from Genelex,

a DNA testing company

Advantages:Maintained by healthcare professionalsInteractions provides a summary of the literatureProvides link to PubMed articles referenced

Disadvantage:Not FDA approved

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PubMed Search for Clerkship Project

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Notes

Notes

GeneMedRx is Growing!!!

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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.

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Special Thanks to Dr. Oesterheld, Dr. Patterson,

Kristine Ashcraft and Howard Coleman

with the Staff at Genelex

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References1. 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. 2008 Sep 5 [cited 2008 Sep 11]. Available from: www.bloodjournal.org

2. 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):825-830.

3. Hamalainen M, Korhonen R, Moilanen E. Calcineurin inhibitors down-regulate iNOS expression by destabilizing mRNA. Int Immunopharmacol. 2008. [cited 2008 Sep 9]. Available from: www.elsevier.com/locate/intimp

4. Lam S, Partovi N, Ting L, Ensom M. Corticosteroid interactions with cyclosporin, tacrolimus, mycophenolate, and sirolimus: fact or fiction? Ann Pharmacother. 2008 Jul/Aug;42;1037-047.

5. 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;40:1690-1695.

6. 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):719-729.

7. Thervet E, Anglicheau D, Legendre C, Beaune P. Role of pharmacogenetics of immunosuppressive drugs in organ transplantation. Ther Drug Monit. 2008 Apr;30(2): 143-150.

8. 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. 2008 Jan;27(1):1-6.

9. 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;21:427-435.

10. 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;28:167-175.

11. 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. 2007 Apr;41:653-658.

12. 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):350-356.

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References1. 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):170-1744.

2. 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;10:474-478.

3. 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;12:552-559.

4. 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. 2006 Feb 2;28:34-42.

5. 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;37:2609-2610.

6. 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;18:757-758.

7. Fireman M, DiMartini A, Armstrong S, Cozza K. Med-psych drug-drug interactions update: immunosuppressants. Psychosomatics. 2004 Jul/Aug;45:354-360.

8. 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.

9. Armstrong S, Cozza K, Pimentel E. Med-psych drug-drug interactions update: immunosuppressants. Psychosomatics. 2002 Sep/Oct;43:424-427.

10. Cvetkovic R, Goa K. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802.

11. 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.

12. 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):441-444. Available from: http://www.jstage.jst.go.jp/browse/dmpk

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References1. 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):477-480.

2. 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;45:1018-1024. Available from: http://www.jclinpharm.org/cgi/content/abstract/45/9/1018

3. 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;14:1263-1275.

4. Dowell J, Stogniew M, Krause D, Henkel T, Damle B. Lack of pharmacokinetic interaction between anidulafungin and tacrolimus. J Clin Pharmacol. 2007;47:305-314. Available from: http://www.jclinpharm.org/cgi/content/abstract/47/3/305

5. Zimmerman J. Exposure-response relationships and drug interactions of sirolimus. AAPS J. 2004;6(4):1-12.

6. Baciewicz A, Chrisman C, Finch C, Self T. Update on rifampin and rifabutin drug interactions. Am J Med Sci. 2008 Feb;335(2):126-136.

7. Kane G, Lipsky J. Drug-grapefruit juice interactions. Mayo Clin Proc. 2000 Sep;75(9):933-942.8. 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: 18769365

9. Golshayan D, Pascual M. Minimization of calcineurin inhibitors to improve long-term outcomes in kidney transplantation. Transpl Immunol. Epub 2008 Sep 2. PMID: 18775494

10. 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: 18482220

11. Anglicheau D, Legendre C, Beaune P, Thervet E. Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics. 2007 Jul;8(7):835-49.

12. 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: 18704002

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References1. Gobernado M, Cantón E. [Anidulafungin]. Article in Spanish. Rev Esp Quimioter. 2008

Jun;21(2):99-114. PMID: 18509769

2. Catalán González M, Montejo González JC. [Anidulafungin: a new therapeutic approach in antifungal therapy. Pharmacology of anidulafungin]. Article in Spanish. Rev Iberoam Micol. 2008 Jun;25(2):92-100. PMID: 18473503

3. 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. 2003 Nov;41(11):499-503.

4. 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):941-52.

5. 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. 2007 Mar-Apr;107(2):215-8.

6. 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.

7. Sirolimus product insert. Wyeth Pharmaceutical Inc. Revised January 2008. Available from: www.wyeth.com

8. Tacrolimus product insert. Astellas Pharma US, Inc. Revised April 2008. Available from: www.fda.gov

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