ABSTRACT ARCHIVE

Background: S-1360, an HIV-1 integrase inhibitor, represents a new class of potent anti-HIV agents, showing in vitro anti-HIV activity with an EC₅₀ of 63 ng/mL. S-1360 is currently under development by Shionogi-GlaxoSmithKline Pharmaceuticals LLC. Methods: A randomized double-blind, placebo-controlled, parallel group, escalating multiple dose study was conducted in healthy volunteers under fed conditions. Subjects were randomized to 500 mg q12h, 1000 mg q12h, 2000 mg q12h, or placebo. Day 1 and Day 14 were single dose; no dose on Day 2; and q12h dosing was administered from Day 3 to Day 13. Plasma was obtained for full PK profiles on Day 1 and Day 14; a single pre-dose sample was obtained on Days 12 and 13. Subject dosing was directly observed on Day 1 through Day 14 (except Day 2 when no dosing occurred). Clinical laboratory evaluations were at pre-dose, Days 5, 9, 16, and at follow-up. ECGs were performed at baseline, on Days 1, 9, and 14 at pre-dose and 2h after morning dose and at follow-up. Results: A total of 24 subjects were enrolled in the study with 18 receiving S-1360 and 6 subjects receiving placebo. On Day 14, mean Cmax ranged from 4.75 μg/mL to 15.6 μg/mL with the median tmax between 2.25 to 3h After reaching Cmax, concentration-time profiles declined in a biexponential manner. The mean terminal elimination t½ ranged from 7.7 to 16 h over the dose range. Repeat dosing q12h did not result in significant accumulation. S-1360 plasma protein binding ranged from 98.23-99.98% in vivo. There were no serious adverse events. During the study, 10 (56%) subjects who had received S-1360 and 3 (50%) subjects who had received placebo experienced mild to moderate treatment emergent adverse events. The most frequent adverse event was headache. Conclusions: S-1360 was well tolerated, and showed acceptable PK profiles. These results support proceeding to clinical studies in HIV seropositive subjects.