TY - JOUR T1 - CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1796 LP - 1802 DO - 10.1124/dmd.114.060194 VL - 42 IS - 11 AU - Yanhui Lu AU - Edward J. Fuchs AU - Craig W. Hendrix AU - Namandjé N. Bumpus Y1 - 2014/11/01 UR - http://dmd.aspetjournals.org/content/42/11/1796.abstract N2 - 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 (AUC0–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 wild-type groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC0–inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC0–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 one-half of African Americans. ER -