PIII-39Safety, tolerability and pharmacokinetics (PK) of multiple doses of lecozotan, a novel 5HT1A antagonist, in healthy elderly subjects

Abstract

BACKGROUND/AIMS Lecozotan is a potent and silent 5-HT1A antagonist being developed for the treatment of cognitive deficits associated with Alzheimer's disease. The objective of this study was to assess the safety, tolerability, and PK of multiple oral doses of Lecozotan in elderly subjects (> 65 yrs old), a population similar to the target patient population. METHODS This was a randomized, double-blind, placebo-controlled study in 16 subjects who received 5 mg q12h of Lecozotan or placebo (12 active, 4 placebo) for 14 days. Safety evaluations included adverse events (AE), vital signs, ECG, and lab tests up to 48 hours after the last dose. A complete PK profile was obtained on days 1 and 14. RESULTS Lecozotan was safe and well tolerated after multiple dosing. Few mild to moderate AEs were recorded in 4 out of 16 subjects. There were no clinically significant changes in vital signs, ECGs, and routine laboratory tests. Lecozotan tmax was < 1 hour and t1/2 was 9 – 11 hours. Steady-state Cl/F was ∼33 mL/h/kg. Steady-state was achieved by day 3 of q12h administration and accumulation ratio was 1.8. Mean steady-state AUC0–12h was within 13% of the mean single-dose AUC0-∞ suggesting reliable multiple-dose predictability from single-dose PK. Cl/F in elderly was ∼ 25% lower in comparison to young subjects. CONCLUSIONS Lecozotan was safe in elderly subjects up to multiple daily doses of 10 mg and the elderly PK profile was characterized by a mild decrease in clearance, which does not justify any dosage adjustment. Clinical Pharmacology & Therapeutics (2005) 79, P68–P68; doi: 10.1016/j.clpt.2005.12.247