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: Petra Hoever, Justin Hay, Mandana Rad, Marzia Cavallaro, Joop M van Gerven, Jasper Dingemanse
• Journal: Journal of clinical psychopharmacology (J Clin Psychopharmacol) Vol. 33 Issue 3 Pg. 363-70 (Jun 2013) ISSN: 1533-712X [Electronic] United States
• PMID: 23609389 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Isoquinolines
• Orexin Receptors
• Pyridines
• Receptors, G-Protein-Coupled
• Receptors, Neuropeptide
• Zolpidem
• almorexant

Topics

• Acetamides (administration & dosage, adverse effects, pharmacokinetics)
• Aged
• Aged, 80 and over
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Half-Life
• Humans
• Isoquinolines (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Middle Aged
• Orexin Receptors
• Pyridines (adverse effects, pharmacokinetics, pharmacology)
• Receptors, G-Protein-Coupled (antagonists & inhibitors)
• Receptors, Neuropeptide (antagonists & inhibitors)
• Sleep Initiation and Maintenance Disorders (drug therapy)
• Zolpidem