Background:  GSK364735 (735) is a potent HIV integrase-strand transfer inhibitor. The aim of this study was to determine single and repeat dose safety, tolerability, and pharmacokinetics of 735 in healthy subjects.

Methods:  This was a double-blind, randomized, parallel, placebo-controlled, phase I study in which we enrolled 79 subjects, 30 in part A, 49 in part B. In part A, 3 alternating cohorts of 10 subjects (8 active, 2 placebo) received single doses of 50 to 400 mg fasting; 200 mg and 400 mg + food,  735 50 mg + ritonavir (RTV) 100 mg, and 735 200 mg + Maalox ES 30 cc. In part B, 5 cohorts received repeat-doses of 100 to 600 mg daily with food for 7 days. CYP450 probes were administered before and after repeat doses of 735 200 mg every 12 hours. Safety was assessed throughout the study. Serial blood samples were analyzed for 735 plasma concentrations using a validated liquid chromatography/mass spectrometry (LC/MS) assay. Pharmacokinetic parameters were estimated using non-compartmental methods.

Results:  The most commonly reported drug-related adverse events (n) were headache (5), abdominal discomfort (3), flatulence (2), loose stool (2), lightheadedness (3), sedation (4), and musculoskeletal pain (3). All were mild, except 1 moderate headache. None were serious or treatment-limiting. No grade 2 or higher laboratory abnormalities or significant changes in vital signs, telemetry, or electrocardiograms were reported.  Preliminary pharmacokinetic parameters (geometric mean [CV%]) are presented in the table. With dose, 735 exposure increased less than proportionally. Food increased 735 exposure by 30 to 100%. RTV did not significantly alter the pharmacokinetics of 735.  Maalox reduced 735 exposure by ~50%. Furthermore, 735 did not inhibit or induce CYP enzyme activities except weak inhibition of CYP1A2, which was not considered clinically significant.

Conclusions:  GSK364735 was safe and well-tolerated, and exposure exceeded therapeutic targets (0.062 µg/mL, protein-shift EC₉₀) and is now in phase II clinical studies in HIV-infected patients.