¹Wyeth Research, 3 Clinical Research, Paris, France

Abstract

Background: SRA-333 is a new potent, silent 5-HT_1A antagonist proposed for the treatment of cognitive deficits associated with Alzheimer's disease.

Methods: This was a single-dose, randomized, double-blind, placebo-controlled, 2-period cross-over study in 48 healthy subjects (8 men and 8 women in each of the following age groups: 18–45, 65–74, and equal or above 75 years) with 5 mg SRA-333. Evaluations consisted of safety and tolerability, pharmacokinetics (PK), and pharmacodynamics using the Cognitive Drug Research Battery (Reading, UK).

Results: SRA-333 was safe and well tolerated in both young and elderly subjects. The incidence of treatment-emergent adverse events in elderly subjects was 50% less than that in young subjects. There were no clinically relevant changes in vital signs, ECG interval or laboratory tests. The t_max for SRA-333 was <1h. Mean t_1/2 increased from 9.5h to 14.4 hr in elderly subjects because of a decrease in oral clearance (17% in men, 25% in women). C_max and AUC were not significantly different between young and elderly subjects, but C_max values were 17% higher in women compared with men, which may be explained by weight differences (mean= 69 vs. 81 kg respectively). SRA-333 had no deleterious effect on attention, vigilance, sensorimotor task or working and episodic memory.

Conclusions: SRA-333 was well tolerated in all age groups. The PK profile of the elderly subjects was characterized by a mild decrease in clearance that did not justify any dosage adjustment.