Immunosuppressant drug interactions with the newer antifungals

June 2004

Drug interactions leading to adverse reactions may account for 2.8% to 26% of hospital admissions. Advanced age, polypharmacy, medications with a narrow therapeutic index or those requiring therapeutic drug monitoring all increase the possibility for a drug interaction to occur (Am J Hosp Pharm. 1989;46:729-732). Based upon these criteria, the transplant recipient falls into a high risk for developing a potential drug interaction. Since infection can be one of the major hurdles to a successful transplantation, potential interactions between anti-infective agents and immunosuppressants always exist.

Invasive fungal infections are frequently observed in the transplant population, carrying with them a substantial mortality rate. Most of these infections are caused by Candida or Aspergillus sp. (Medicine [Baltimore]. 1999;78:123-138). Recently, two novel antifungals — voriconazole (Vfend, Pfizer), a triazole antifungal, and caspofungin (Cancidas, Merck), an echinocandin — have been shown to be effective in the treatment of Aspergillus and Candida infections.

Both immunosuppressant and antifungal medications are metabolized through the cytochrome P450 (CYP450) enzyme system, which predispose them to potential interactions. The CYP450 enzymes belong to a superfamily of oxygenases, whose primary purpose is to add a functional group to a drug to increase its polarity and promote its excretion from the body. If enzymes possess more than 40% homology, they are grouped together into families, designated by an Arabic numeral (eg, the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (eg, CYP2C and CYP2D subfamilies); members of each subfamily have more than 55% homology with one another. Individual members are given an additional number (eg, CYP3A4) to identify a specific enzyme pathway. CYP3A4 is of particular importance, since over 60% of oxidized drugs undergo biotransformation through this enzyme system (Clin Pharmacokinet. 2000;38:41-57; J Am Acad Dermatol. 2002;47:467-484; quiz 485-488).

Metabolism

Oral cyclosporine has incomplete absorption with a large interpatient variability, which is relative to liver function, presence of bile salts, administration of food and gastrointestinal tract status. Cyclosporine is extensively metabolized by the hepatic and intestinal CYP450 3A enzyme system (Clin Pharmacokinet. 1996;30:141-179). Oral tacrolimus is a macrolide immunosuppressant with erratic absorption from the small intestine and a poor, highly variable oral bioavailability (4%-89%). Metabolism occurs in the liver and intestinal mucosa primarily through the CYP3A4, and most of both the parent drug and its metabolites are excreted in the bile (Clin Pharmacokinet1995;29:404-430). In the case of the newer antifungals, voriconazole is a substrate for the CYP450 2C9, 2C19 and 3A4. Caspofungin, however, undergoes N-acetylation and hydrolysis with slow minimal biotransformation. Unlike voriconazole, available data suggest that caspofungin does not inhibit any enzyme in the CYP450 system.

Voriconazole

In a randomized, double-blind, placebo-controlled trial of kidney transplant recipients, Romero et al found that voriconazole (200 mg orally every 12 hours for 7.5 days) increased cyclosporine area under the curve (AUC) by 1.7-fold and mean cyclosporine trough concentrations by 2.48-fold (Clin Pharmacol Ther. 2002;71:226-234). Voriconazole may also increase tacrolimus trough concentrations 10-fold. In a liver transplant recipient, voriconazole 200 mg twice daily increased steady-state tacrolimus concentrations of 2.3 ng/mL to 12.5 ng/mL and 23.5 ng/mL after three and five days, respectively (Antimicrob Agents Chemother. 2002;46:3091-3093). While not specifically reported with voriconazole, fluconazole (in doses greater than 200 mg) may increase sirolimus trough concentrations two to three-fold. Therefore, a similar interaction would be expected with voriconazole (Transplantation. 1994;57:1521-1523). Based upon these data, cyclosporine, tacrolimus and sirolimus trough concentrations should be monitored closely during the first two weeks of initiating or discontinuing voriconazole therapy. Package labeling recommends that cyclosporine dose be reduced by 50% and tacrolimus dose by at least 33% prior to initiating voriconazole therapy. While no specific recommendations exist for sirolimus, the sirolimus dose may also be empirically decreased by 20% to 50%.

Caspofungin

While caspofungin has not been found to be a substrate for or inhibitor of the CYP450 enzyme system, drug interactions have been documented for both cyclosporine and tacrolimus. From pharmacokinetic and phase-1 studies, patients who were receiving concomitant cyclosporine and voriconazole exhibited an increase in caspofungin AUC by 35%, possibly leading to transient but clinically significant elevations in liver transaminases. Currently, package labeling recommends caspofungin not be administered with cyclosporine. However, a single-center study of 16 allogeneic stem cell transplant recipients found that the concurrent use of caspofungin and cyclosporine had no attributable adverse effects (caspofungin package insert). Until further studies are conducted, caution is warranted when administering caspofungin with cyclosporine. Liver function tests should be monitored closely with this combination.

In another phase-1 study of allogeneic stem cell transplant recipients, caspofungin reduced tacrolimus AUC by 20%, and 12-hour blood concentration by 26%, with a small transient increase in alanine aminotransferase. Tacrolimus concentrations and liver function tests should be closely monitored when caspofungin is coadministered and tacrolimus dose adjusted accordingly (caspofungin package insert).

Since many drug interactions go undetected, the infectious disease clinician needs to be proactive rather than reactive in identifying potentially serious drug interactions, particularly in the transplant population.

For more information:

• Koecheler JA, Abramowitz PW, Swim SE, Daniels CE. Indicators for the selection of ambulatory patients who warrant pharmacist monitoring. Am J Hosp Pharm. 1989;46:729-732.
• Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore). 1999;78:123-138.
• Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41-57.
• Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;47:467-484; quiz 485-488.
• Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically significant drug interactions with cyclosporin. An update. Clin Pharmacokinet.1996;30:141-179.
• Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29:404-430.
• Romero AJ, Pogamp PL, Nilsson LG, Wood N. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther. 2002;71:226-234.
• Venkataramanan R, Zang S, Gayowski T, Singh N. Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes. Antimicrob Agents Chemother. 2002;46:3091-3093.
• Manez R, Martin M, Raman D, et al. Fluconazole therapy in transplant recipients receiving FK506. Transplantation. 1994;57:1521-1523.
• Voriconazole, Vfend package insert. Pfizer. New York. January 2003.
• Caspofungin, Cancidas package inert. Merck. North Wales, Pa. April 2003.

• Robert Lee Page II, PharmD, BCPS, is an assistant professor of clinical pharmacy, and a clinical specialist in Cardiology/Heart Transplant at the University of Colorado School of Pharmacy.