341 Acute effects of seltorexant, a selective orexin-2 antagonist (JNJ- 42847922), on driving after bedtime administration

Abstract

Abstract Introduction Seltorexant (JNJ-42847922), a potent and selective antagonist of the human orexin-2 receptor, is being developed for the treatment of major depressive disorder. Seltorexant also has sleep-promoting properties. Investigating the effects of sleep-promoting medications on driving is important because some of these agents (e.g. GABAA receptor agonists) may be associated with increased risk of motor vehicle accidents. We evaluated the effect of seltorexant on driving after forced awakening at night, using a validated driving simulator. Methods This double-blind, placebo and active-controlled, randomized, 3-way cross-over study was conducted in 18 male and 18 female healthy subjects. All subjects received seltorexant 40 mg, zolpidem 10 mg, or placebo 15 minutes before bedtime. Eighteen subjects were awakened at 2- and 6-hours post-dose, and the other 18 at 4- and 8-hours post-dose. At those timepoints, pharmacokinetics, objective (standard deviation of the lateral position [SDLP]) and subjective effects (using Perceived Driving Quality and Effort Scales) on driving ability, postural stability and subjective sleepiness were assessed. Results For seltorexant, the SDLP difference from placebo (95% confidence interval) at 2-, 4-, 6- and 8-hours post-dose was 3.9 cm (1.26, 6.60), 0.9 cm (-1.08, 2.92), 1.1 cm (-0.42, 2.63), and 0.6 cm (-2.75, 1.55), respectively vs. 9.6 cm (6.97, 12.38), 6.6 cm (3.53, 9.60), 4.7 cm (1.46, 7.85), and 1.3cm (-1.16, 3.80), respectively for zolpidem. The difference from placebo was significant at 2-hours after taking seltorexant, while the difference from placebo was significant at 2, 4 and 6-hours after zolpidem. Subjective driving quality was decreased for both drugs at all time points and driving effort was increased up to 4-hours post-dose for both medications. Subjective sleepiness showed a significant increase compared to placebo 2- and 4-hours after administration of either drug. Postural stability was decreased up to 2-hours after administration of seltorexant, and up to 4-hours after administration of zolpidem. Conclusion Compared to zolpidem, objective effects on driving performance were more transient after seltorexant administration and largely normalized by 4–6 hours post-dose. Support (if any) This work was sponsored by Janssen R&D.