¹Wyeth Pharmaceuticals, Wyeth Research, Cemax, Collegeville, PA

Abstract

Background/aims: Lecozotan is a new potent and silent 5-HT_1A antagonist being developed for the treatment of cognitive deficits associated with Alzheimer's disease. Pharmacokinetics (PK) and brain receptor occupancy data currently justify a twice-daily dosing regimen with the immediate release (IR) formulation and there is a need to develop a modified release formulation to allow once-daily dosing of Lecozotan. The objective of this study was to assess the relative bioavailability of 3 new sustained/modified release (SR) formulations compared to the IR formulation.

Methods: This was a single-dose, randomized, 4-period, crossover study in 20 subjects who received 5 mg of all 4 (1 IR and 3 SR) formulations. Lecozotan PK parameters were compared between the 4 formulations using statistical analyses.

Results: Based on AUC_0-, the SR-fast and SR-medium formulations were bioequivalent to the IR formulation. C_max with the SR-fast and SR-medium formulations was 1/3^rd that of the IR formulation. C_max/C_24h ratios for the SR-fast and SR-medium formulations were 2.8 and 2.3, respectively, in comparison to 23 for the IR formulation. Treatment-emergent adverse events were substantially less frequent with the SR formulations (1 vs. 14 for IR), presumably because of reduced C_max.

Conclusions: Bioequivalence with the IR formulation suggests that the SR-fast and SR-medium formulations are suitable for further development and the low C_max/C_24h ratios show favorable properties for once daily administration.