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.
Footnotes
- Received July 24, 2014.
- Accepted August 12, 2014.
This research was supported by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), which is funded in part by the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) [Grant UL1TR001079], a component of the NIH, and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Johns Hopkins ICTR, NCATS, or NIH. The AB SCIEX QTRAP5500 Quadrupole-Linear Ion Trap console was purchased with proceeds from the NIH National Center for Research Resources [Grant 1S10RR27733 (to W.C.H.)]. The Waters Acquity ultra-performance liquid chromatograph interfaced with mass spectrometry was purchased with funds from Pendleton Enterprises [(to C.W.H.)].
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics