title: 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 (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.
authors.affiliation: Department of Pharmacology and Molecular Sciences (Y.L., C.W.H., N.N.B.), and Division of Clinical Pharmacology, Department of Medicine (E.J.F., C.W.H.), Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Molecular Sciences (Y.L., C.W.H., N.N.B.), and Division of Clinical Pharmacology, Department of Medicine (E.J.F., C.W.H.), Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fuchs
authors.affiliation: Department of Pharmacology and Molecular Sciences (Y.L., C.W.H., N.N.B.), and Division of Clinical Pharmacology, Department of Medicine (E.J.F., C.W.H.), Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.affiliation: Department of Pharmacology and Molecular Sciences (Y.L., C.W.H., N.N.B.), and Division of Clinical Pharmacology, Department of Medicine (E.J.F., C.W.H.), Johns Hopkins University School of Medicine, Baltimore, Maryland nbumpus1@jhmi.edu.
authors.forename: Namandjé N
authors.initials: NN
authors.lastname: Bumpus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001483:Base Sequence; D003510:Cyclohexanes / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D017931:DNA Primers; D023581:HIV Fusion Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000077592:Maraviroc; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D003510:Cyclohexanes; D017931:DNA Primers; D023581:HIV Fusion Inhibitors; D014230:Triazoles; D051544:Cytochrome P-450 CYP3A; D000077592:Maraviroc