Orexin Receptor Antagonism, a New Sleep-Promoting Paradigm: An Ascending Single-Dose Study With Almorexant

Almorexant, a dual orexin receptor antagonist potentially representing a new class of sleep-promoting compounds, was administered in an ascending single-dose study to evaluate tolerability, pharmacokinetics, and pharmacodynamics. Seventy healthy male subjects were enrolled in this double-blind, placebo-and active-controlled study. Each dose level (1-1,000 mg) was investigated in a separate group of 10 subjects (6 on almorexant, 2 on placebo, 2 on zolpidem 10 mg). Almorexant was well tolerated with no signs of cataplexy. Peak plasma concentration (C-max) was quickly attained (median time to maximum concentration (t(max)) ranged from 0.7 to 2.3 h), and plasma concentrations subsequently decreased quickly to similar to 20% of C-max over the course of 8 h. Vigilance, alertness, and visuomotor and motor coordination were reduced following daytime administration of zolpidem or almorexant at doses of >= 400 mg. Population pharmacokinetic/pharmacodynamic modeling suggested that doses of similar to 500 mg almorexant and 10 mg zolpidem are equivalent with respect to subjectively assessed alertness.