Pharmacokinetics and Safety of Seltorexant, a Selective Orexin-2 Receptor Antagonist, in Healthy Elderly and Young Non-Asian, and Japanese Adult Participants

Background: Seltorexant, a selective human orexin-2 receptor antagonist, is being developed for adjunctive treatment of major depressive disorder with insomnia symptoms. This phase 1 study (NCT02837692) explored pharmacokinetics (PK) and safety of seltorexant in healthy elderly and young non-Asian, and Japanese adult participants.

Methods: This study enrolled healthy elderly non-Asian (≥65 years; N&#3f30), weight- and gender-matched young non-Asian (18-45 years; N&#3f80), and Japanese participants (20-60 years; N&#3f30) to different cohorts, each receiving a single oral seltorexant dose (10-120 mg). PK and safety were assessed.

Results: Young and elderly non-Asian participants receiving a single dose (10-40 mg) exhibited dose-proportional increases in PK for seltorexant and its metabolites (M12 and M16). Higher doses (60-120 mg) in young non-Asian participants showed linear, but less than dose-proportional increases in PK for seltorexant and its metabolites. Seltorexant and metabolite PK parameters were comparable between elderly and young non-Asian participants receiving seltorexant 20 and 40 mg. Japanese adult participants exhibited dose-proportional increases after a single seltorexant dose (10-40 mg), and PK parameters were comparable between Japanese and young non-Asian participants. No clear dose-related trends in treatment-emergent adverse events were observed for single doses up to 40 mg in elderly non-Asian and healthy Japanese adult participants, and up to 120 mg in healthy young non-Asian participants.

Conclusions: Seltorexant demonstrated dose-linear PK, with dose proportionality between 10 and 40 mg. Age or Japanese descent had no apparent impact on seltorexant PK. Seltorexant showed no new safety concern and was generally well tolerated in different subpopulations of healthy participants.