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Use of hypnotics is often associated with next‐morning residual effects and a higher risk of motor vehicle accidents. Measuring next‐morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50–79 years of age) were randomized in a placebo‐ and active‐controlled, four‐way cross‐over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo‐corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46–3.93) and 4.43 cm (2.72–6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self‐rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non‐insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them. [ABSTRACT FROM AUTHOR]

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 14C‐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. [ABSTRACT FROM AUTHOR]

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