¹Pfizer Global Research and Development, Neurocrine Biosciences, Ann Arbor, MI

Abstract

Background/aims: To describe the dose-response relationship of indiplon on subjectively measured wake after sleep onset (sWASO), a measure of time spent awake after initially falling asleep thus assessing sleep maintenance; to determine the impact of covariates and assess time course of response.

Methods: Data from 2 crossover Phase 2 and 4 parallel Phase 3 studies in insomnia patients were pooled. SWASO was measured daily for up to 3 months. Doses ranged from 5 to 40 mg. Dose-response was modeled using NONMEM. An external validation was conducted.

Results: A total of 2187 patients were included, with a mean age of 55 years and 62% women. Baseline sWASO was dependent on age, gender, and study grouping. Dose response showed a decrease (improvement) in sWASO with dose with ED50=17 mg and reaching a minimum value Emin=56 min; drug response was greater with MR and in women. Drug effect was sustained over time, while a modest decrease in sWASO was observed with placebo. Observed mean sWASO from an independent study (0 and 15 mg in elderly patients) were slightly lower than simulations (100 simulated trials) although within the confidence intervals.

Conclusions: sWASO decreased with increasing indiplon doses, and suggests that doses of 5-15 mg are optimal. Increased benefit is observed at doses higher than 10 mg. The MR formulation provides increased benefit over the IR formulation. Elderly differ in both disease severity and sensitivity, and a lower dose may be required in this population.