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Pharmacokinetic Interaction Between Voriconazole and Efavirenz at Steady State in Healthy Male Subjects

From the Department of Clinical Pharmacology (Dr Liu, Dr Sharma) and Department of Biostatistics (Mr LaBadie), Pfizer Global Research and Development, Groton/New London, Connecticut; Department of Clinical Sciences, Pfizer, Inc, New York (Dr Foster); and Comprehensive NeuroScience, Inc, Ft Lauderdale, Florida (Dr Gutierrez).

A randomized, placebo-controlled (with respect to voriconazole), 2-period, multiple-dose intragroup fixed-dose sequence study was conducted in 34 healthy male subjects to evaluate the interactions between voriconazole (triazole antifungal agent) and efavirenz (reverse transcriptase inhibitor). In period 1, subjects received 200 mg twice-daily (bid) voriconazole (n = 17) or placebo (n = 17) for 3 days (400-mg bid loading doses on day 1). In period 2, following a 7-day washout, subjects received 400 mg once-daily (qd) efavirenz alone for 10 days (days 11-20). Then efavirenz was coadministered with 200 mg bid voriconazole or placebo for the next 9 days (days 21-29). Serial plasma voriconazole and efavirenz concentrations were measured on days 3, 19, and 29, and the safety data were collected throughout the study. The 400-mg qd efavirenz dose substantially reduced the steady-state mean voriconazole area under the curve over the dosing interval (AUC_0-12) by 80% (90% confidence interval [CI], 75%-84%) and peak concentration (C_max) by 66% (90% CI, 57%-73%). The decrease in voriconazole exposure during coadministration is probably mainly due to the induction of CYP2C19 and CYP2C9 by efavirenz. The 200 mg bid voriconazole increased the steady-state mean AUC_0-24 and C_max of efavirenz by 43% (90% CI, 36%-51%) and 37% (90% CI, 29%-46%), respectively. The increase in efavirenz exposure during coadministration is probably due to the inhibition of CYP3A4 by voriconazole. Coadministration of 200 mg bid voriconazole with 400 mg (or higher) qd efavirenz is contraindicated due to the clinically significant effect of efavirenz on voriconazole pharmacokinetics.

Key Words: Voriconazole • efavirenz • pharmacokinetic

Address for reprints: Ping Liu, PhD, Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue, MS6025-A3232, New London, CT 06320; e-mail: Ping.Liu{at}pfizer.com.

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