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

Abstract

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 (AUC0-12) by 80% (90% confidence interval [CI], 75%-84%) and peak concentration (Cmax) 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 AUC0-24 and Cmax 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.

Influence of Efavirenz and Nevirapine on the Pharmacodynamics and Pharmacokinetics of Gliclazide in Rabbits

“…As per the literature, administration of multiple doses of efavirenz results in decreased exposure in humans and animals, suggesting an autoinduction of efavirenz metabolism [29,32,33,36,37]. The plasma half-life of efavirenz in animals is approximately 0.8 to 1.9 h compared to more than 40 h in humans [38,39].…”

“…In vitro and in vivo studies demonstrated that efavirenz is a potent inducer of CYP3A4 in a concentration-and time-dependent manner [22,32,33]. Clinical drug-drug interaction studies showed that efavirenz signifi cantly induced CYP enzymes and decreased the concentration levels of several CYP3A4 [34,35] substrates predominantly and, CYP2C9 and CY-P2C19 substrates partly [36]. Enzyme induction has important clinical implications when enhanced drug metabolism results in lower drug concentrations, which leads to a suboptimal effi cacious response or, even worse, the development of drug resistance.…”

Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A

“…Although findings from in vivo studies are generally limited, our in vitro data are consistent with the findings of in vivo studies that showed that voriconazole interacts with certain CYP2B6 substrates. Voriconazole has recently been reported to significantly slow the elimination of efavirenz in healthy volunteers (37). Although the authors of that study (37) suggested that CYP3A was the mechanism for this interaction, the available in vitro evidence (9,66) on May 9, 2018 by guest http://aac.asm.org/ efavirenz and that inhibition of CYP2B6 is the main mechanism by which voriconazole increases efavirenz exposure in humans (37).…”

“…Several clinical studies and case reports have documented that voriconazole substantially reduces the clearance of several drugs, including warfarin (49), phenytoin (48), midazolam (53), diazepam (52), immunosuppressant drugs (cyclosporine, sirolimus, and tacrolimus) (46,47), efavirenz (37), methadone (36), ibuprofen (27), diclofenac (26), fentanyl and alfentanil (54), oxycodone (22), and omeprazole (47). Considering the mechanisms of clearance of the drugs affected (3), many of these drug-drug interactions appear to be attributable to pharmacokinetic changes that can be understood in terms of inhibition of the cytochrome P450 (CYP) system.…”

“…Comprehensive inhibitory analyses that encompass all major drug-metabolizing CYPs are important because not all pharmacokinetic drug interactions involving voriconazole can be explained by the CYPs studied so far. For example, voriconazole has recently been shown to slow the elimination of efavirenz (37), a drug mainly metabolized by CYP2B6 (9,66).…”