Abstract

Cytochrome P450 3A5 (CYP3A5) plays a prominent role in oxidative metabolism of maraviroc, an approved drug for HIV-1 treatment and a candidate for HIV-1 prevention. We studied the effect of CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild type allele *1 and non-functional mutant alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in 3 groups (N = 8 each): mutant, heterozygous, and homozygous wild type. Subjects received an oral 300-mg maraviroc dose followed by blood collection for 32 h. The homozygous wild type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curve from time 0 to infinity (AUC_0-inf) was 2099 (1422-2568) ng·h/mL, 1761 (931-2640) ng·h/mL and 1238 (1065-1407) ng·h/mL, respectively, for the mutant, heterozygous, and homozygous wild type groups. The homozygous wild type group had 41% lower maraviroc AUC_0-inf, 66% higher apparent clearance, and 78% higher apparent volume of distribution, compared with mutant group (P ≤ 0.02). The AUC_0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild type group were lower by 51% and 64% when compared with the mutant group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild type group indicated that maraviroc may be under-dosed in people homozygous for CYP3A5*1 allele which includes almost a half of African Americans.