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

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

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

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

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:10.1038/ncpneph0343

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

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route Tacrolimus Sirolimus Chloramphenicol Unknown (possibly UGT) Clotrimazole CYP3A4, possibly P-gp CYP3A4 Mibefradil (withdrawn) CYP3A4, CYP2D6 Danazol, Cimetidine, Metoclopramide, Bromocriptine, Protease inhibitors, Nicardipine, Cisapride CYP3A4 and/or P-gp Felodipine, Lansoprazole,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

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

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

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

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

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

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

Notes

Notes

GeneMedRx is Growing!!!

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.

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

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