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 ~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 > or =400 mg. Population pharmacokinetic/pharmacodynamic modeling suggested that doses of ~500 mg almorexant and 10 mg zolpidem are equivalent with respect to subjectively assessed alertness.