Accelerated Development of the Dual Orexin Receptor Antagonist ACT-541468: Integration of a Microtracer in a First-in-Human Study.
Clin Pharmacol Ther
; 104(5): 1022-1029, 2018 11.
Article
em En
| MEDLINE
| ID: mdl-29446069
ABSTRACT
The orexin system regulates sleep and arousal and is targeted by ACT-541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5-200 mg to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a 14 C-labeled, orally and intravenously (i.v.) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax ) of 0.8-2.8 h and geometric mean terminal half-life (t1/2 ) of 5.9-8.8 h. Clear dose-related effects on the central nervous system were observed at ≥25 mg, indicating a suitable PK-PD profile for a sleep-promoting drug, allowing for rapid onset and duration of action limited to the intended use. This comprehensive first-in-human study created a wealth of data, while saving resources in drug development.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
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Vigília
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Antagonistas dos Receptores de Orexina
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Medicamentos Indutores do Sono
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Imidazóis
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article