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Pharmacokinetic Interaction Between Voriconazole and Efavirenz at Steady State in Healthy Male Subjects
Author(s) -
Liu Ping,
Foster Grover,
LaBadie Rober R.,
Gutierrez Mari J.,
Sharma Amarnath
Publication year - 2008
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270007309703
Subject(s) - voriconazole , efavirenz , pharmacokinetics , placebo , pharmacology , crossover study , dosing , medicine , confidence interval , drug interaction , area under the curve , anesthesia , gastroenterology , viral load , immunology , human immunodeficiency virus (hiv) , antifungal , alternative medicine , pathology , dermatology , antiretroviral therapy
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.