Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers

Abstract

Cytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t1/2) and increased both the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 h to t (AUC0-t) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P < 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC0-t ranged from 0.4% to ∼224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P < 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC0-t (Pearson r = >0.8; P < 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selective in vivo probe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability. (This study is registered at ClinicalTrials.gov under identifier NCT01104376.).

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Time course of plasma concentrations of efavirenz (EFV) (A), 8-hydroxy-EFV (8-OHEFV) (B), di-OHEFV (C), and 7-OHEFV (D) in healthy volunteers after a single 100-mg oral dose alone (○) or after treatment with voriconazole to steady state (●). The insets for EFV represent log-transformed concentration-time profile of EFV (A) or plasma concentration-time profiles of metabolites from 0 to 24 h (B, C, and D).

FIG 2

Percent changes in maximum concentration (Cmax) and partial area under the plasma concentration-versus-time curve (AUC) of efavirenz (EFV) metabolites in healthy volunteers after a single 100-mg oral dose of EFV without (control) and with voriconazole treatment to steady state. Percent changes of 8-hydroxy-EFV (8-OHEFV), 7-OHEFV, and di-OHEFV were calculated as 100 × (voriconazole − control)/control. Except for changes in AUC0–t of 8-OHEFV and Cmax of 7-OHEFV, which did not reach a statistically significant level, all other parameters were significantly altered by voriconazole (P < 0.05).

FIG 3

Time course of plasma efavirenz (EFV)-to-metabolite concentration ratios after the administration of a single 100-mg oral dose of EFV at baseline (○) and after treatment with voriconazole (●) to steady state. (A) EFV/8-hydroxy-EFV (8-OHEFV); (B) EFV/di-OHEFV; (C) EFV/(8-OHEFV + di-OHEFV); (D) EFV/7-OHEFV.

FIG 4

Correlation of the 3-hour concentration ratios of efavirenz (EFV) to 8-hydroxy-EFV (8-OHEFV) with EFV exposure (A) and partial area under the plasma concentration-versus-time curve (AUC) metabolic ratios (MRs) (B) following a single 100-mg oral dose of EFV alone (○) and after treatment with voriconazole to steady state (●).

FIG 5

Proposed mechanisms for increased efavirenz (EFV) exposure by voriconazole (Vori). The di-OHEFV formed from 8-OHEFV represents 8,14-di-OHEFV, while the di-OHEFV formed from 7- and 8-OHEFV represents 7,8-di-OHEFV. OH, hydroxyl.