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Entry‐into‐humans study with ACT‐462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant
Author(s) -
Hoch Matthias,
van Gorsel Helene,
van Gerven Joop,
Dingemanse Jasper
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.297
Subject(s) - orexin receptor , pharmacodynamics , antagonist , placebo , medicine , anesthesia , crossover study , pharmacology , pharmacokinetics , orexin , receptor , alternative medicine , pathology , neuropeptide
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 t max 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.