title: Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant.
abstract: A double-blind, placebo- and active comparator-controlled, randomized, single-ascending-dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT-462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT-462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400-mg group received a single oral dose of 400 mg almorexant (two-way crossover). ACT-462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose-dependent. ACT-462206 was absorbed with a median tmax of 1.5-4.0 hours. The elimination half-life varied from 4.8 to 11.2 hours. A clinically relevant reduction in vigilance and attention, alertness, and motor coordination was recorded at ACT-462206 doses ≥200 mg. The onset was between 20 and 45 minutes after drug intake, the maximum effect between 1 and 2 hours after drug administration, and these impairing effects largely disappeared within 8 hours post-dose. Doses of 400-1,000 mg ACT-462206 were similarly efficacious to 400 mg almorexant, with a trend for an earlier onset of action with ACT-462206. The present results confirm the activity of ACT-462206 as an orexin antagonist.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123, Allschwil, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoch
authors.forename: Helene
authors.initials: H
authors.lastname: van Gorsel
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D001288:Attention / Q000187:drug effects; D004311:Double-Blind Method; D006801:Humans; D006993:Hypnotics and Sedatives; D007546:Isoquinolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D000068796:Orexin Receptor Antagonists; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011759:Pyrrolidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012438:Saccades / Q000187:drug effects; D012894:Sleep Stages / Q000187:drug effects; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects; D055815:Young Adult
chemical_list: C000596436:ACT-462206; D000081:Acetamides; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; D011759:Pyrrolidines; D013449:Sulfonamides; C519150:almorexant
keywords: almorexant; orexin; pharmacodynamics; pharmacokinetics; sleep disorders