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 (AUC 0-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 wildtype groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC 0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC 0-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 onehalf of African Americans.

Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures

“…This is consistent with recent data in human liver microsomes (HLMs) showing that the estimated CYP3A5 contribution to maraviroc metabolism in HLMs from wild-type CYP3A5 *1/*1 donors (homozygous functional allele) was 32% compared with only 2% in HLMs from CYP3A5 *3/*3 donors (homozygous dysfunctional allele) (Tseng et al, 2014). Lu et al (2014) also concluded that maraviroc may be underdosed in patients who are homozygous for the CYP3A5*1 allele, which includes nearly one-half of all black individuals (Xie et al, 2004;Abel et al, 2008;Lu et al, 2014). Lu and colleagues are the first to present results on the effect that the CYP3A5 genotype has on maraviroc pharmacokinetics (PK).…”

“…Exposure-response analyses from the maraviroc phase 3 trials (MERIT and MOTIVATE studies) show a flat response with maraviroc C avg above 75-100 ng/ml (McFadyen et al, 2008;Jacqmin et al, 2013). Therefore, the exposures achieved in the homozygous wild-type CYP3A5 group as reported in the Lu et al (2014) study should be sufficient for virologic response given that the median (interquartile range) maraviroc C avg was 103 ng/ml (90-117). The maraviroc dose of 300 mg BID should provide near-maximal efficacy across the range of exposures when given in combination therapy.…”

“…A recent publication by Lu et al (2014) described the effects of the CYP3A5 genotype on Selzentry/Celsentri (maraviroc) concentrations. Maraviroc is a chemokine (C-C motif) receptor 5 inhibitor approved for the treatment of human immunodeficiency virus (HIV) infection (Dorr et al, 2005).…”

Off-label use of maraviroc in clinical practice

“…[22] Nonetheless, not always the use of MVC supports its use as a therapeutic strategy. [23] In this case, MVC failed to demonstrate its efficacy to treat patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Among the possible explanation might be that selective CCR5 antagonism could be insufficient to significantly improve the measures assessed in the study and that CCR5 may not be a relevant mechanism in the progression of this disease.…”

“…Among the possible explanation might be that selective CCR5 antagonism could be insufficient to significantly improve the measures assessed in the study and that CCR5 may not be a relevant mechanism in the progression of this disease. [23] However, far from considering that this is not a useful therapeutic option in some diseases, we should wonder many questions. For example, are present other countervailing chemokines that would be now responsible for maintaining the damage?…”