L iver transplantation has enhanced the overall life expectancy for patients with end-stage liver diseases. 1 However, transplant recipients must receive life- long treatment with immunosuppressive drugs to avoid graft rejection, and this may increase the risk of many infections, including invasive fungal infections. 2 Most immunosuppressants are primari- ly metabolized in the liver and in the gut by the CYP3A4 isoenzyme, so that con- comitant treatment with CYP3A4 modu- lators may result in clinically relevant pharmacokinetic drug– drug interactions. 3 Of note, azole antifungals, which are currently among the mainstay of treat- ments for invasive fungal infections in sol- id organ transplant patients, 2,4 are potent inhibitors of CYP3A4 activity. 5 Several studies and reports showed significant im- pairment of clearance for cyclosporine, tacrolimus, or sirolimus in patients receiv- ing antifungal treatment with either keto- conazole, itraconazole, fluconazole, posa- conazole, or voriconazole. 5,6 Accordingly, significant dosage reductions of the im- munosuppressants, coupled with intensive therapeutic drug monitoring (TDM) of their blood concentrations, are recom- mended to avoid overexposure and drug- related toxicity risk during azole cotreat- ment in transplant recipients. Everolimus is a macrolide immuno- suppressant analog of sirolimus classified as a proliferation signal inhibitor acting on the mammalian target of ra- pamycin (mTOR). 7 It is currently under investigation in the US as an agent to prevent acute and chronic rejection in transplant patients. Although the definitive adult dosage has not been established, results from early clinical trials sug- gest that initial oral dosages of 1–1.5 mg every 12 hours, Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient Federico Pea, Umberto Baccarani, Marcello Tavio, Piergiorgio Cojutti, Gian Luigi Adani, Angela Londero, Massimo Baraldo, Loretta Franceschi, Mario Furlanut, and Pierluigi Viale Author information provided at the end of the text. The Annals of Pharmacotherapy ■ 2008 November, Volume 42 ■ 1711 www.theannals.com OBJECTIVE: To describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. CASE SUMMARY: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (C min ) of everolimus was achieved (~5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus C min averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, C min reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean ± SD, 3.49 ± 0.29 vs 11.05 ± 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patient’s condition continued to deteriorate and he died on day 84 posttransplant. DISCUSSION: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The interaction is due to the inhibition of CYP3A4-mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. CONCLUSIONS: Our data suggest that during everolimus–azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment. KEY WORDS: drug interaction, everolimus, fluconazole, liver transplantation, therapeutic drug monitoring, voriconazole. Ann Pharmacother 2008;42:1711-6. Published Online, 23 Sept 2008, www.theannals.com, DOI 10.1345/aph.1L330 by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from