title: Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects.
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.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Hoever
authors.forename: Justin
authors.initials: J
authors.lastname: Hay
authors.forename: Mandana
authors.initials: M
authors.lastname: Rad
authors.forename: Marzia
authors.initials: M
authors.lastname: Cavallaro
authors.forename: Joop M
authors.initials: JM
authors.lastname: van Gerven
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D064446:Orexin Receptors; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy; D000077334:Zolpidem
chemical_list: D000081:Acetamides; D007546:Isoquinolines; D064446:Orexin Receptors; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D000077334:Zolpidem; C519150:almorexant