Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist

• Published in: Journal of psychopharmacology (Oxford) 2012-08, Vol.26 (8), p.1058-1070
• Main Authors: Bettica, Paolo, Nucci, Gianluca, Pyke, Caroline, Squassante, Lisa, Zamuner, Stefano, Ratti, Emiliangelo, Gomeni, Roberto, Alexander, Robert
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antagonist drugs; Arousal - drug effects; Benzofurans - adverse effects; Benzofurans - pharmacokinetics; Benzofurans - pharmacology; Biological and medical sciences; Circadian rhythms; Clinical trials; Cognition - drug effects; Cognitive ability; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Dose-Response Relationship, Drug; Drug dosages; Drug Interactions; Drug therapy; Drugs; Electroencephalography - drug effects; Fatigue; Half-Life; Humans; Hypnotics; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - pharmacokinetics; Hypnotics and Sedatives - pharmacology; Integration; Male; Medical sciences; Middle Aged; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Orexin Receptors; Orexins; Pharmacodynamics; Pharmacokinetics; Pharmacology. Drug treatments; Polysomnography - drug effects; Population studies; Psychopharmacology; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, Neuropeptide - antagonists & inhibitors; Simvastatin; Simvastatin - pharmacokinetics; Single-Blind Method; Sleep; Sleep - drug effects; Sleep and wakefulness; Sleep disorders; Sleep Stages - drug effects; Thiazoles - adverse effects; Thiazoles - pharmacokinetics; Thiazoles - pharmacology; Wakefulness - drug effects
• ISSN: 0269-8811; 1461-7285
• DOI: 10.1177/0269881111408954

The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation study (dose range: 10–80 mg in the fed and fasted states) and a multiple repeat dose study (dose range: 5–30 mg in the fed state) enrolling a total of 103 male volunteer subjects. SB-649868 was well tolerated at all doses in this study population, with mechanism-related adverse events (e.g. somnolence and fatigue) observed in a majority of subjects after 60 and 80 mg single doses. Although total drug exposure was similar in the fed and fasted states, the rate, but not the extent, of absorption increased in the fed state, resulting in an increased Cmax. The typical estimated half-life of SB-649868 was 3–6 h – comparable with currently used hypnotic agents. Repeated administration of SB-649868 dose-dependently increased exposure to simvastatin (10 mg), suggesting CYP3A4 inhibition ranging from very mild (5 mg) to strong (30 mg). Evening dosing resulted in significant dose-dependent improvement in latency to persistent sleep, total sleep time and wake after sleep onset as measured by polysomnography. Next-morning testing did not detect evidence of residual cognitive effects. Results of these trials support further investigation of SB-649868 and other dual orexin receptor antagonists as potentially effective and well-tolerated treatments for patients with sleep disorders.