Orexin receptor antagonism: an ascending multiple-dose study with almorexant.
The objectives of this study were to investigate the multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual orexin receptor antagonist almorexant. Healthy subjects received daily doses of almorexant (100, 200, 400 or 1000 mg) or placebo in the morning for four days followed by two days with evening administration (Days 5-6). Each dose level was investigated in a new group of 10 subjects (eight active, two placebo, 1:1 sex). Dose-dependent increases in frequency and intensity were observed for somnolence and other adverse events. Pharmacokinetics at steady state showed rapid absorption, low concentrations eight hours post-dose, and minimal accumulation. Following evening, administration absorption was delayed and C(max) decreased. Almorexant at 400 and 1000 mg administered in the morning reduced vigilance, alertness, visuomotor coordination, and motor coordination assessed in a psychometric test battery. Polysomnography recordings following evening administration showed a trend towards shorter latency to sleep stages 3 and 4, and shorter latency to, and longer time in, rapid-eye-movement sleep at higher doses when compared to placebo. Whether these findings in healthy subjects translate into relevant sleep-enabling effects in insomnia patients needs to be investigated in future studies.
Department ofClinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, Switzerland.
Petra
P
Hoever
Sanne L
SL
de Haas
Georg
G
Dorffner
Eleonora
E
Chiossi
Joop M
JM
van Gerven
Jasper
J
Dingemanse
D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D058256:Brain Waves / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D064446:Orexin Receptors; D017286:Polysomnography / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D012894:Sleep Stages / Q000187:drug effects
D000081:Acetamides; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C519150:almorexant