¹Wyeth Pharmaceuticals France, Division Wyeth Research, Wyeth Research, Uppsala University PET Center, Quintiles AB, Paris - La Deéfense Cedex, France

Abstract

Background/aims: L, a potent and silent 5HT_1A antagonist, is being developed for the treatment of Alzheimer's disease (AD). This study, which used the immediate release (IR) formulation, was conducted to assess L binding to 5HT_1A receptors in human brain using PET and WAY-100635 as tracer, in order to guide dose selection for Phase 2 studies with the sustained release (SR) formulation.

Methods: A single dose of 0.5, 1, or 5 mg lecozotan-IR was administered to healthy young subjects and a single dose of 5 mg was administered to elderly subjects and AD patients to assess possible binding differences due to age/disease. L C_plasma-receptor occupancy (RO) relationship was described using an E_max pharmacodynamic model by means of a population approach. Based on this model, peak and trough RO were predicted for various regimens of the 2 formulations.

Results: After single 0.5, 1, and 5 mg doses to young subjects, the average temporal cortex 5-HT1A RO increased in a dose-dependent manner (10%, 18%, 44%, respectively). After a single oral dose of 5 mg lecozotan, maximum RO, seen at t_max of lecozotan, was 44% in young, 63% in elderly and 55% in AD populations. The SR formulation is predicted to produce steady state peak/trough RO of approximately 37%/19%, 57%/36%, and 71%/53% with 2, 5 and 10 mg QD, respectively.

Conclusions: These results demonstrate that Lecozotan is predicted to produce similar 5HT1A RO with a QD dose of SR formulation as with a BID dose of IR formulation.