In vivo individual variations in pharmacokinetics of efavirenz in cynomolgus monkeys genotyped for cytochrome P450 2C9

Cynomolgus monkeys are used frequently in preclinical studies for new drug development due to their evolutionary closeness to humans. An antiretroviral drug, efavirenz, is a typical probe substrate for human cytochrome P450 (P450) 2B6, but is mainly metabolized by cynomolgus monkey P450 2C9. In this study, plasma concentrations of efavirenz were assessed in six cynomolgus monkeys genotyped for P450 2C9 c.334A>C (I112L) (three wild-type, one heterozygote and two homozygotes) by high performance liquid chromatography with tandem mass spectrometry. After intravenous administration at a dose of 1.0mg/kg, biphasic plasma elimination curves of efavirenz were seen in these cynomolgus monkeys. The mean plasma concentration of the primary metabolite 8-hydroxyefavirenz (1h after treatment, with hydrolysis by -glucuronidase) in the wild-type group was significantly higher (4.0-fold) than the combined heterozygous and homozygous group mean. The area under the plasma concentration-time curve value of efavirenz in the homozygous group after oral administration at a dose of 2.0mg/kg was significantly higher (2.0-fold) than the combined wild-type and heterozygous group. These results collectively indicated that P450 2C9 c.334A>C (I112L) variation was associated with efavirenz metabolic clearance in vivo. Cynomolgus P450 2C9 polymorphism might account for interindividual variations of efavirenz metabolism in cynomolgus monkeys. Copyright (c) 2016 John Wiley & Sons, Ltd.