CYP3A5 genotype impacts Maraviroc concentrations in healthy volunteers

Abstract

CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the 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 dysfunctional alleles ∗2, ∗3, ∗6, and ∗7) to obtain 24 evaluable subjects in three groups (n = 8 each): homozygous dysfunctional (two dysfunctional alleles), heterozygous (one ∗1 allele and one dysfunctional allele), and homozygous wild-type (two ∗1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. 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 curves from time 0 to infinity (AUC 0-inf) were 2099 (1422-2568) ng h/ml, 1761 (931-2640) ng h/ml, and 1238 (1065-1407) ng h/ml for the homozygous dysfunctional, heterozygous, and homozygous wildtype groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC 0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC 0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5 1 allele, including almost onehalf of African Americans.