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 aC-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) of 0.8-2.8 h and geometric mean terminal half-life (t) of 5.9 to 8.8 h. Clear dose-related effects on the central nervous system (CNS) 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-humans (FIH) study created a wealth of data while saving resources in drug development. This article is protected by copyright. All rights reserved.