Abstract Body

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 Cmax, AUCtau, and C12 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 Cmax, AUCtau, and C12 by ~50%, ~60%, and ~90%, respectively, consistent with CYP3A inhibition by ritonavir (RTV). ETR decreased BMS-626529 Cmax, AUCtau, and C12 each by ~50%, consistent with CYP3A induction by ETR. DRV/r + ETR increased BMS-626529 Cmax, AUCtau, and C12 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.

Conclusions: BMS-663068 can be co-administered with DRV/r or DRV/r + ETR, without dose adjustment. Co-administration with ETR (without DRV/r) resulted in a ~50% decrease in BMS-626529 C12 levels. Skin rash was consistent with ETR and DRV/r administration.

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PK results of BMS-626529 when coadministered with DRV/r and/or ETR