CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

1 Univ of Liverpool, Liverpool, UK, 2 St. Stephen’s AIDS Trust, Chelsea and Westminster Hosp, London, UK, 3 Univ of Turin, Turin, Italy Background: Rilpivirine (RPV) is mainly metabolised by cytochrome P450 (CYP) enzymes but less is known about the importance of transporters in its disposition. Many enzymes and transporters are transcriptionally regulated by the pregnane-X-receptor (PXR; NR1I2). In this study, we sought to determine associations between genetic variants within the ) from 150 patients receiving RPV-containing regimens recruited in Turin (Italy) and London (UK). Plasma concentrations of RPV were analysed by validated LC-MS/MS methods. Genotyping was conducted by real-time PCR-based allelic discrimination using standard methods for the following polymorphisms: CYP3A4*22 (rs35599367), CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), NR1I2 (rs2472677), SLC22A1 (rs628031, rs72552763, rs622342 and rs683369), SLCO2B1 (rs1077858, rs12422149, rs35199625, rs2712807 and rs2851069). Data were log transformed, and univariate and multivariate linear 171.4 (80.9) ng. mL -1 . 86%were male, 98%were white, 74.7% received emtricitabine with tenofovir disoproxil fumarate (FTC/TDF), 23.3% received ritonavir-boosted darunavir (DRV/r), and 2% received abacavir with lamivudine (ABC/3TC). All SNPs were in Hardy-Weinberg equilibrium and carrier/non-carrier analyses were applied in regression analyses. In univariate linear regression, differences in C 12 were associated with height (P= 0.01) and CYP3A4*22 (P= 0.01). Differences in C 12 were also seen between patients receiving different backbone therapies. CYP3A4*22 (P= 0.02, β= -0.17), and concomitant drugs (P= 0.02, β= -0.09) remained significant in multivariate linear regression (see table). Conclusion: These results indicate that CYP3A4*22 (c.522-191 C>T; rs35599367) is associated with RPV pharmacokinetics but further studies are required to confirm this association. While the impact of CYP3A4*22 on C 12 was relatively minor, a more marked effect would be expected after administration of the RPV long-acting depot and this warrants further investigation. genes coding for these proteins and RPV plasma concentrations. Methods: Blood samples were collected 12 hours post dose (C 12 regression was used to investigate associations. All data are given as mean with standard deviation. Results: Patients were 42.7 (11.1) years old, with height 173.5 (8.3) cm, weight 72.3 (12.4) kg and C 12

Poster and Themed Discussion Abstracts

417 EFFECT OF CYP3A5 GENOTYPE ON THE PK OF MARAVIROC AND METABOLITES IN HEALTHY SUBJECTS Manoli Vourvahis 1 , Sunil Nepal 2 , Annie Fang 1 , Gwendolyn Fate 3 , Linda S. Wood 3 , Jean-Claude Marshall 3 , Andrew Clark 4 , Jayvant Heera 3 1 Pfizer, New York, NY, USA, 2 Pfizer, Biostatistics, Collville, PA, USA, 3 Pfizer, Groton, CT, USA, 4 ViiV Hlthcare, London, UK

Background: Maraviroc (MVC) is a substrate for CYP3A, P-gp and OATP1B1. Previous data demonstrated that MVC average exposures (Cavg) are lower in subjects with the CYP3A5 (3A5)*1/*1 wild-type/extensive metabolizer (EM) genotype (GT) (n=8) compared to those with 3A5 mutant alleles (*3, *6 and/or *7; poor metabolizer (PM); n=8). While rare in Caucasians (CAU), the prevalence of EMs is substantial (39-70%) in Blacks. Thus, the aimwas to describe the prevalence and assess the effect of 3A5 GT on the pharmacokinetics (PK) of MVC and metabolites in healthy African-American (AA) and CAU subjects when MVC was dosed alone or with darunavir/cobicistat (DRV/c). MVC and metabolite PK comparisons were assessed by 3A5 GT with and without DRV/c and between race. Methods: This was an open-label, parallel group study targeting 12 healthy adults per cohort. Subjects were enrolled by 3A5 GT and race into: Cohort 1–AA with no 3A5*1 alleles (PM); Cohort 2–AA with one 3A5*1 allele (intermediate metabolizer; IM); Cohort 3–AA with two 3A5*1 alleles (EM); or Cohort 4–CAU with no 3A5*1 alleles (PM). For Part 1, all subjects received MVC 300 mg BID for 5 days. For Part 2 (Cohorts 1 and 3), subjects received MVC 150 mg QD in combination with DRV/c for 10 days. Serial PK sampling followed the last dose of MVC in Part 1 and 2. Results: 47 subjects were enrolled. MVC and metabolite PK, when dosed alone, are summarized in the Table. Mean MVC Cavg were ranked highest to lowest by 3A5 GT, PM>IM>EM. EMs had 37% and 26% lower MVC Cavg compared to AA PMs and CAU PMs, respectively. Comparing the impact of race, AA PMs had 17% higher exposures as compared to CAU PMs. PF-06857639 was the only MVC metabolite shown to be affected by 3A5 GT. When MVC was co-administered with DRV/c, AA EMs had an 18% lower MVC Cavg compared to AA PMs and metabolites were undetectable in most samples. There were no serious or severe adverse events. Conclusion: 3A5 GT, not race, had the most influence on MVC exposure and the magnitude of the 3A5 GT effect on MVC Cavg was reduced in the presence of DRV/c, a potent CYP3A inhibitor. Lower MVC PK associated with 3A5 EMs are not expected to be clinically relevant for treatment of HIV, regardless of 3A5 GT, as MVC exposures associated with MVC efficacy (Cavg ≥75 ng/mL) was achieved in all subjects with MVC 300 mg BID alone and MVC 150 mg QD with DRV/c and was not shown to impact efficacy in a previous presentation of the Phase 3 MERIT study. Maraviroc dosing with/without DRV/c was well tolerated.

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