¹Wyeth Pharmaceuticals France, Division WyethResearch, Wyeth Research, Wyeth, Biotrial, Aster-Cephac, Paris - La Deéfense Cedex, France

Abstract

Background/aims: Lecozotan is a potent and silent 5-HT_1A 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 t_max was < 1 hour and t_1/2 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 AUC_0-12h was within 13% of the mean single-dose AUC_0- 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.