Original ContributionsTolerability, Pharmacokinetics, and Pharmacodynamics of Single-Dose Almorexant, an Orexin Receptor Antagonist, in Healthy Elderly SubjectsHoever, Petra MSc*; Hay, Justin PhD†; Rad, Mandana MD†; Cavallaro, Marzia MSc‡; van Gerven, Joop M. MD, PhD†; Dingemanse, Jasper PhD, PharmD, FCP* Author Information From the *Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; †Centre for Human Drug Research (CHDR), Leiden, The Netherlands; and ‡Department of Biometry, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. Received November 4, 2011; accepted after revision August 31, 2012. Reprints: Jasper Dingemanse, PhD, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland (e-mail: [email protected]). This Centre received funding from Actelion Pharmaceuticals Ltd for the clinical conduct of this study. Journal of Clinical Psychopharmacology 33(3):p 363-370, June 2013. | DOI: 10.1097/JCP.0b013e31828f5a7a Buy Metrics Abstract Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects. In this double-blind, placebo- and active-controlled study, each dose (100, 200, and 400 mg) was investigated in a separate group of 12 subjects (almorexant, placebo, and zolpidem 10 mg in an 8:2:2 ratio). Morning doses of almorexant were well tolerated. As expected for sleep-enabling compounds, somnolence and fatigue were frequently reported. Other adverse events included headache and nausea. Muscular weakness was reported at a higher incidence only with the highest almorexant dose. The pharmacokinetic profile of almorexant was characterized by a median time to the maximum concentration of 1.5 hours, quick disposition with a distribution half-life of 1.6 hours, and rapidly decreasing concentrations to approximately 20% of the maximum concentration over 8 hours, with a terminal half-life of 32 hours. Objective pharmacodynamic measures showed decreases in saccadic peak velocity and adaptive tracking performance and increases in body sway with the 400-mg dose of almorexant. Subjective assessments revealed a dose-dependent decrease in alertness. Almorexant had no effects on mood, calmness, subjective internal and external perception, and feeling high. These findings provide a solid basis to study the effects of almorexant in elderly patients with insomnia. © 2013 Lippincott Williams & Wilkins, Inc.