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Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Clinical Pharmacologist, Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine, Italy

Umberto Baccarani, MD

Researcher, Department of Surgery and Transplantation, Medical School, University of Udine

Marcello Tavio, MD

Infectivologist, Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine

Piergiorgio Cojutti, MD

Postgraduate Fellow, Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine

Gian Luigi Adani, MD

Surgeon, Department of Surgery and Transplantation, Medical School, University of Udine

Angela Londero, MD

Postgraduate Fellow, Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine

Massimo Baraldo, MD

Associate Professor, Pharmacology; Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine

Loretta Franceschi, BSc

Researcher, Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine

Mario Furlanut, MD

Professor, Pharmacology; Director, Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine

Pierluigi Viale, MD

Professor, Infectious Diseases; Director, Clinic of Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of Udine

Reprints: Dr. Pea, Institute of Clinical Pharmacology & Toxicology, DPMSC, University of Udine, P.le S. Maria della Misericordia 3, 33100 Udine, Italy, fax 39 0432 559819, pea.federico{at}aoud.sanita.fvg.it

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

Published Online, September 23, 2008. www.theannals.com, DOI 10.1345/aph.1L330