No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects.

Abstract

Maraviroc is a C-C chemokine receptor type-5 antagonist approved for the treatment of HIV-1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism. The presence of 2 functional alleles (CYP3A5*1/*1) confers the extensive metabolism phenotype, which is rare in whites but common in blacks. The effect of CYP3A5 genotype on maraviroc and/or metabolite pharmacokinetics was evaluated in 2 clinical studies: a post hoc analysis from a phase 2b/3 study (NCT00098293) conducted in 494 HIV-1-infected subjects (study 1) in which the impact on maraviroc efficacy in 303 subjects was also assessed, and a study conducted in 47 healthy volunteers (study 2). In study 2 (NCT02625207), extensive metabolizers had 26% to 37% lower mean area under the concentration-time curve compared with poor metabolizers (no CYP3A5*1 alleles). This effect diminished to 17% in the presence of potent CYP3A inhibition. The effect of CYP3A5 genotype was greatest in the formation of the metabolite (1S,2S)-2-hydroxymaraviroc. In study 1, the CYP3A5*1/*1 genotype unexpectedly had higher maraviroc area under the curve predictions (20%) compared with those with no CYP3A5*1 alleles. The reason for this disparity remains unclear. The proportions of subjects with viral loads <50 and <400 copies/mL for maraviroc were comparable among all 3 CYP3A5 genotypes. In both studies maraviroc exposures were in the range of near-maximal viral inhibition in the majority of subjects. These results demonstrate that although CYP3A5 contributes to the metabolism of maraviroc, CYP3A5 genotype does not affect the clinical response to maraviroc in combination treatment of HIV-1 infection at approved doses.

• Authors: Manoli Vourvahis, Lynn McFadyen, Sunil Nepal, Srinivas Rao Valluri, Annie Fang, Gwendolyn D Fate, Linda S Wood, Jean-Claude Marshall, Phylinda L S Chan, Angus Nedderman, Julian Haynes, Mark E Savage, Andrew Clark, Kimberly Y Smith, Jayvant Heera
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 59 Issue 1 Pg. 139-152 (01 2019) ISSN: 1552-4604 [Electronic] England
• PMID: 30192390 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Chemical References

• HIV Fusion Inhibitors
• CYP3A5 protein, human
• Cytochrome P-450 CYP3A
• Maraviroc

Topics

• Adult
• Cytochrome P-450 CYP3A (genetics)
• Double-Blind Method
• Female
• Genotype
• HIV Fusion Inhibitors (blood, pharmacokinetics, therapeutic use)
• HIV Infections (drug therapy, genetics, metabolism)
• HIV-1
• Healthy Volunteers
• Humans
• Male
• Maraviroc (blood, pharmacokinetics, therapeutic use)
• Middle Aged
• Polymorphism, Genetic
• Treatment Outcome
• Young Adult