PIII‐70

BACKGROUND/AIMS To assess the safety, tolerability and pharmacokinetics of single ascending doses of rotigaptide, a first‐in‐class cardiomyocyte gap junction modifier, in healthy subjects. METHODS In a randomized, double‐blind, placebo‐controlled, sequential‐group study, ascending single doses of rotigaptide or placebo were administered to 79 men as a 24‐hour IV infusion of 0.03 to 30 mg or as a bolus of 2 or 3 mg. Safety was determined from reported adverse events (AEs), physical exams, vital signs, laboratory tests, and 12‐lead ECGs. Plasma and urine samples were analyzed for rotigaptide using LC/MS/MS method and rotigaptide pharmacokinetics was characterized. RESULTS The most common AEs were asymptomatic orthostatic increase in pulse (n=28) and decrease in blood pressure (n=4), and local irritation, rash, and/or blistering at the electrode site (n=23). All were considered by the investigator as mild or moderate and probably not related to test article. There were no dose‐related trends in AEs or laboratory tests. Rotigaptide disposition was characterized by low Cl (133 mL/min) and low V SS (21.4 L) and the terminal disposition t 1/2 was 2.7 h. AUC increased in a dose‐proportional manner. Approximately 61–84% excreted unchanged in urine and no metabolites were apparent in plasma. CONCLUSION Rotigaptide appeared to be safe and well‐tolerated at the doses tested in healthy subjects. Rotigaptide showed predictable0 and linear pharmacokinetics and renal excretion was the primary route of elimination. Clinical Pharmacology & Therapeutics (2005) 79 , P77–P77; doi: 10.1016/j.clpt.2005.12.278