CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Methods: This was an open-label, 2-period, fixed-sequence study in healthy adult men (n=11). In Period 1, a SD of 100 mg doravirine was administered on Day 1. In Period 2, following a 7-day washout, a SD of 600 mg rifampin and 100 mg doravirine were coadministered on Day 1. Following a 3-day washout, 600 mg rifampin was administered once daily for 15 days (Days 4-18) and 100 mg doravirine was coadministered on Day 17. Safety evaluations were performed throughout the study. Results: There were no serious clinical or laboratory adverse experiences (AEs) and all reported AEs were judged as mild in intensity. Following coadministration of single doses of rifampin and doravirine, the geometric mean ratio (GMR) (90% confidence interval [CI]) (doravirine + SD rifampin/doravirine) for AUC0- ∞ and C24 were 0.91 (0.78, 1.06) and 0.90 (0.80, 1.01), respectively, suggesting that OATP1B1 inhibition does not impact the PK of doravirine. The GMR (90% CI) for Cmax were 1.40 (1.21, 1.63), indicating that P-gp inhibition may increase doravirine Cmax. After coadministration with multiple doses of rifampin, doravirine concentrations were significantly reduced as expected based on the role of CYP3A4 in doravirine metabolism. The GMRs (doravirine +MD rifampin/doravirine) and 90% CIs for AUC0- ∞ , C24, and Cmax were 0.12 (0.10, 0.15), 0.03 (0.02, 0.04), and 0.43 (0.35, 0.52), respectively. Conclusions: Doravirine was generally well tolerated when administered alone or with rifampin. Inhibition of OATP1B1 and P-gp by SD rifampin did not have a clinically meaningful effect on the PK of doravirine. Multiple dosing of rifampin significantly reduced doravirine AUC0- ∞ , Cmax and C24. Thus, doravirine should not be administered with strong CYP3A4 inducers. 522 Drug-Drug Interaction Between HCV Inhibitors Grazoprevir/Elbasvir With Dolutegravir Background: Grazoprevir (MK-5172) is a potent, once-daily inhibitor of the hepatitis C virus (HCV) NS3/4A protease and elbasvir (MK-8742) is a potent, once-daily HCV NS5A replication complex inhibitor that are being developed as a fixed-dose combination therapy for the treatment of chronic HCV infection in mono- and HCV/human immunodeficiency virus (HIV)-coinfected patients. This study evaluated the safety and pharmacokinetic (PK) interactions of grazoprevir and elbasvir when coadministered with dolutegravir (DTG), a HIV-1 integrase strand transfer inhibitor in healthy volunteers. Methods: This was an openlabel, 2period, fixedsequence study in 12 healthy adult males and females. In period 1, a single dose (SD) of 50 mg DTG was administered, followed by a 3-day washout. In period 2, 200 mg grazoprevir + 50 mg elbasvir were administered once daily on days 111, with a SD of 50 mg DTG coadministered on day 9. PK assessments for DTG were performed on day 1 of period 1 and day 9 of period 2, and for grazoprevir and elbasvir on days 8 and 9 of period 2. Safety assessments included electrocardiograms, vital signs, clinical laboratory tests, physical examination, and adverse event (AE) monitoring. Results: Grazoprevir + elbasvir had no clinically meaningful effect on the DTG PK, with AUC 0- ∞ and C 24 1.34) and 1.14 (0.95, 1.36), respectively. Similarly, the elbasvir PK were not affected by coadministration of DTG, with AUC 0-24 , C max , and C 24 (0.89, 1.05), and 0.98 (0.93, 1.03), respectively. However, DTG did result in decreased grazoprevir PK with AUC 0-24, C max, and C 24 GMRs (90% CIs) of 0.81 (0.67, 0.97), 0.64 (0.44, 0.93), and 0.86 (0.79, 0.93), respectively. Coadministration of grazoprevir + elbasvir with DTG was generally well tolerated in the healthy subjects. The most common drug-related AEs were dyspepsia, headache, and sinus congestion, which were mild and resolved by study end. Conclusions: Coadministration of grazoprevir + elbasvir with DTG had no clinically meaningful effect on the PK of DTG or elbasvir. Coadministration of DTG with grazoprevir + elbasvir decreased grazoprevir PK. However, the decrease in grazoprevir PK was within the therapeutic window currently defined for grazoprevir. These results suggest that no geometric mean ratios (GMRs) (90% confidence intervals [CIs]) of 1.16 (1.00, GMRs (90% CIs) of 0.98 (0.93, 1.04), 0.97 Background: BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T-cells. Phase 2b data (through Week 24) show BMS-663068 has similar efficacy to ATV/r (both combined with RAL+TDF) in treatment-experienced (TE), HIV-1-infected subjects (sbj). Darunavir/ritonavir (DRV/r) and etravirine (ETR) use is common among TE patients. As the CYP3A4 metabolic pathway contributes to the metabolism of BMS-626529, and DRV/r and ETR are also metabolized by or alter CYP3A4 activity, there is potential for drug-drug interactions. Methods: AI438020 was an open-label, single-sequence, multiple-dose, three cohort study in 42 healthy sbj (n=14 per cohort). BMS-663068 was given at 600mg BID (A), DRV/r at 600mg/100mg BID (B), and ETR at 200mg BID (C). Dosing in each cohort was on Days 1–4, 7–16, and 17–26, with a 2-day washout (WO) on Days 5 and 6. Treatment order in each cohort was: Cohort 1: A (WO), then B, followed by A+B; Cohort 2: A (WO), then C, followed by A+C; Cohort 3: A (WO), then B+C, followed by A+B+C. PK parameters were derived using non–compartmental methods. Geometric mean ratios and 90% confidence intervals (CI) were calculated from log-transformed C max , AUC tau , and C 12 using mixed-effect modeling, with limits of 0.75–1.70 and 0.8–1.25 predefined for ETR and DRV/r, and BMS-663068 use respectively. Safety measurements included vital signs and adverse event monitoring. Results: Compared to BMS-663068 BID alone, co-administration with DRV/r increased BMS-626529 C max , AUC tau , and C 12 by ~50%, ~60%, and ~90%, respectively, consistent with CYP3A inhibition by ritonavir (RTV). ETR decreased BMS-626529 C max , AUC tau , and C 12 each by ~50%, consistent with CYP3A induction by ETR. DRV/r + ETR increased BMS-626529 C max , AUC tau , and C 12 by ~50%, ~30%, and ~30%, respectively, consistent with RTV inhibition of CYP3A predominating over ETR induction (Table). Conversely, BMS-626529 caused minimal changes to the PK of DRV/r, ETR or DRV/r + ETR, and were within predefined no-effect limits. BMS-663068 was generally well tolerated. Skin rash (Grade 1–2) was reported in 28.3% of sbj and considered related to ETR and DRV/r, not to BMS-663068. Wendy W. Yeh 1 ;Ted Marenco 2 ; Hwa-Ping Feng 1 ; Zifang Guo 1 ; Daria Stypinski 2 ; Lisa Ross 3 ; Ivy H. Song 4 ; Patricia Jumes 1 ; Barbara Cook 2 ; Joan R. Butterton 1 1 Merck & Co, Inc, Boston, MA, US; 2 Celerion, Lincoln, NE, US; 3 ViiV Healthcare, Research Triangle Park, NC, US; 4 GlaxoSmithKline, Research Triangle Park, NC, US dose adjustments in grazoprevir, elbasvir, or DTG are needed for coadministration in coinfected patients. 523 HIV-1 Attachment Inhibitor Prodrug BMS-663068: Interactions with DRV/r and/or ETR Ishani Savant Landry ; XiaoluTao; Jeffrey Anderson; Michael Hesney; Michele Stonier; Susan Lubin; JianWang; George J. Hanna; DavidW. Boulton Bristol-Myers Squibb, Princeton, NJ, US

Poster Abstracts

342

CROI 2015