CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: Numerous antiretrovirals showed inhibition of SLC22A1 in vitro . Particularly noticeable was the predominance of SLC22A1 inhibitors in the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes. Maximum patient plasma concentrations of efavirenz (12.9 m M) and darunavir/r (11.9 m M) are lower than the SLC22A1 IC 50 s determined. Efavirenz showed moderately higher but statistically significant accumulation in SLC22A1-expressing cells. These data inform the mechanistic basis for disposition, drug-drug interactions and pharmacogenetic candidate gene selection for antiretroviral drugs. 520 EFV but Not ATV/r Significantly Reduces Atovaquone Concentrations in HIV+ Subjects Monica M. Calderon 4 ; Joseph A. Kovacs 2 ; Alice K. Pau 2 ; Maryellen McManus 2 ; Raul Alfaro 1 ; Parag Kumar 1 ; Scott R. Penzak 3 1 National Institutes of Health (NIH), Bethesda, MD, US; 2 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US; 3 University of North Texas System College of Pharmacy, Forth Worth, TX, US; 4 US Food and Drug Administration (FDA), Silver Spring, MD, US Background: Atovaquone is an alternative agent for prophylaxis and treatment of PCP and toxoplasmosis. Previous studies have shown that average steady state atovaquone concentrations (C avg ) ≥ 14 μ g/mL and ≥ 18.5 μ g/mL are predictive of successful treatment of PCP and toxoplasmosis, respectively. In a recent study, atovaquone exposure following a single dose of atovaquone/proguanil was reduced by 46-75% in HIV+ patients receiving EFV, LPV/r or ATV/r compared to HIV- controls receiving no ART. The current study was conducted to determine if similar pharmacokinetic (PK) interactions occur in HIV+ subjects receiving atovaquone oral suspension at doses used in the treatment of PCP or toxoplasmosis. Methods: 30 HIV+ volunteers were recruited, 10 each taking EFV-based ART, ATV/r-based ART, or no ART. Subjects were randomly assigned to atovaquone 750 mg BID with food for 14 days (Phase 1) followed (after a washout period) by atovaquone 1500 mg BID with food for 14 days (Phase 2), or vice versa. On day 14 of each phase, blood samples were collected over 12 hrs to determine atovaquone PK parameter values including area under the concentration-time curve [AUC t ] and C avg using non-compartmental methods. PK parameter values from the EFV and ATV/r arms were compared to the no ART arm using an unpaired t-test. Results: 29 of 30 subjects (25 males; mean age: 42 ± 11 yrs) completed both dosing cohorts. HIV-RNA was < 50 copies/mL in all subjects in the EFV and ATV/r-based ART groups. Median (range) HIV-RNA in the no ART group was 1224 (<40-26,743) copies/mL. Median (range) CD4+ counts in the EFV, ATV/r, and no ART-based groups were 602 (212-1321), 616 (357-916), and 585 (412-912) cells/mm 3 , respectively. Geometric means with 90% CIs are presented for AUC t and C avg . Geometric mean ratios (GMR) are also included for EFV vs. no ART, and ATV/r vs. no ART.

Poster Abstracts

Atovaquone PK alone, and in combination with ATV/r or EFV in HIV+Volunteers Conclusions: Subjects on EFV-based ART had 47% and 44% lower atovaquone exposure than no ART subjects at atovaquone doses of 750 mg BID and 1500 mg BID, respectively ( P <0.01 for each). Moreover, 4 of 10 subjects (40%) on EFV-based ART + atovaquone 750 mg BID had an atovaquone C avg <14 μ g/mL – the concentration associated with successful PCP treatment. In contrast, ATV/r PK parameter values did not differ significantly from control group values at either of the studied doses. These data suggest that the current recommended dose of atovaquone 750 mg BID for PCP treatment may not be adequate in all patients receiving concurrent EFV. 521 The Effect of Single and Multiple Dose Rifampin on the Pharmacokinetics of Doravirine Ka Lai Yee 3 ; Sauzanne G. Khalilieh 2 ; Rachael Liu 3 ; Rosa Sanchez 3 ; Matt S. Anderson 4 ; Candice Smith-Bradley 5 ; Joan Butterton 6 ;Timothy Judge 1 ; Helen Manthos 1 ; John Brejda 1 1 Celerion, Lincoln, NE, US; 2 Merck and Co, Inc, Kenilworth, NJ, US; 3 Merck and Co., Inc., West Point, PA, US; 4 Merck and Co, Inc, Rahway, NJ, US; 5 Merck and Co, Inc, Upper Gwynedd, PA, US; 6 Merck and Co, Inc, Boston, MA, US Background: Doravirine is a novel, potent, HIV-1 non-nucleoside reverse transcriptase inhibitor that is primarily metabolized by oxidation via CYP3A4. Based on in vitro data, doravirine is a substrate of P-gp but not of OATP1B1. This study assessed the impact of single dose (SD) and multiple dose (MD) rifampin administration on the pharmacokinetics (PK) of doravirine. After multiple dosing, rifampin is a strong inducer of CYP3A4, while SD administration of rifampin was performed to assess the effects of hepatic OATP1B1 inhibition and intestinal P-gp inhibition on the absorption and metabolism of doravirine.

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CROI 2015