Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects

J Clin Psychopharmacol. 2013 Jun;33(3):363-70. doi: 10.1097/JCP.0b013e31828f5a7a.


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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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