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

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.

The use of 96-well Scintiplates to facilitate definitive metabolism studies for drug candidates.

Semi-quantitative analysis of the drug-related components in biological samples collected during definitive metabolism studies using radiolabelled drug candidates is commonly achieved by HPLC profiling, using either on-line radiochemical detection or off-line liquid scintillation counting (LSC) following collection of the HPLC eluent into vials. However, although the use of LSC with vials has high sensitivity, the approach is time-consuming, laborious and destructive, whilst on-line detection methods are inappropriate for samples with low-levels of radioactivity (commonly the case with plasma samples). The use of 96-well microtitre plates (Scintiplates) for fraction collection during HPLC profiling provides a sensitive, effective and efficient alternative method for the semi-quantitative analysis of radiolabelled components in biological samples. Furthermore, the approach is non-destructive, such that subsequent identification of the isolated components can be achieved. Although the Scintiplate methodology is not appropriate for the analysis of excreta samples, where quenching of the radiochemical signal by endogenous components was observed, the approach was demonstrated to be valid for the relative quantification of [14C]-labelled material in plasma samples for all species investigated. In addition, good sensitivity was observed, with a counting efficiency of 79% for [14C], such that a drug-related component accounting for 10-15 dpm is quantifiable. The utility of the methodology for profiling circulating metabolites was demonstrated by the analysis of a rat plasma sample following oral administration of [14C]-UK-349,862. The Scintiplate approach and subsequent mass spectrometric analysis resulted in the relative quantitation and specific characterisation of circulating metabolites accounting for 93% of the total plasma radioactivity.