Randomized, Double-Blind, Placebo-Controlled, Single Intravenous Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Novel Coronary Smooth Muscle Cell Proliferation Inhibitor Biolimus A9 in Healthy Individuals.

Biolimus A9 (BA9) is a novel proliferation inhibitor of coronary smooth muscle cells that has been specifically designed for coating drug-eluting stents. The goals of this study were to identify the highest safe intravenous dose of BA9, to evaluate the dose-dependent pharmacokinetics of BA9 after intravenous administration in humans, and to characterize early clinical symptoms of BA9 toxicity in healthy subjects. This phase 1 trial in healthy subjects was designed as a double-blind, placebo-controlled, randomized, ascending single-dose study. After screening and randomization, 28 volunteers received either placebo (n = 7) or BA9 (n = 21) in a double-blinded fashion. Doses from 0.0075 mg/kg were escalated to 0.25 mg/kg in 4 cohorts. BA9 concentrations were measured using liquid chromatography-tandem mass spectrometry. BA9 doses up to 0.075 mg/kg were well tolerated. Only the highest BA9 dose of 0.25 mg/kg produced reversible drug-related adverse events. The most frequent adverse events were headache, nausea, and mouth ulcers, most likely due to immunosuppression. Exposure to BA9 did not result in electrocardiographic or clinical laboratory changes. BA9 had a terminal half-life of 90.0 ± 40.0 hours (all n = 21, mean ± standard deviation), an apparent clearance from blood of 0.96 ± 1.07 L/kg/h, and a volume of distribution of 96.5 ± 72.6 L/kg.