RT Journal Article
SR Electronic
T1 CYP3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1796
OP 1802
DO 10.1124/dmd.114.060194
VO 42
IS 11
A1 Yanhui Lu
A1 Edward J. Fuchs
A1 Craig W. Hendrix
A1 Namandjé N. Bumpus
YR 2014
UL http://dmd.aspetjournals.org/content/42/11/1796.abstract
AB 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.