Accelerated Development of the Dual Orexin Receptor Antagonist ACT-541468: Integration of a Microtracer in a First-in-Human Study

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 C-14-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 (t(max)) of 0.8-2.8 h and geometric mean terminal half-life (t(1/2)) of 5.9-8.8 h. Clear dose-related effects on the central nervous system were observed at >= 25mg, 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.