0008 Night-Time Administration Of ACT-541468, A Novel Dual Orexin Receptor Antagonist: Characterization Of Its Pharmacokinetics, Next-Day Residual Effects, Safety, And Tolerability

Abstract

ACT-541468 is a potent dual orexin receptor antagonist. The orexin system regulates sleep and arousal and is targeted by ACT-541468. Night-time pharmacokinetics (PK), next-day residual effects, safety, and tolerability following evening administration of ACT-541468 were investigated. Double-blind, placebo-controlled, randomized, repeated-dose study in 20 young adult healthy male and female subjects (16/4 active/placebo) following evening administration of 25 mg ACT-541468 for 7 days. PK were assessed in the evening (trough), in the morning (8 h post-dose), and on Day 8 with a PK profile during the elimination phase of the drug to determine the half-life (t½). Four subjects had an additional 8th study drug administration to determine PK parameters at night. Next-day pharmacodynamic (PD) effects (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analog scale (VAS), Digit Symbol Substitution Test (DSST), Simple Reaction Time Test (SRTT), Karolinska Sleepiness Scale (KSS), Leeds Sleep Evaluation Questionnaire (LSEQ), and VAS Bowdle for evaluation of psychedelic effects) were assessed in the morning. During the night subjects were not disturbed. Plasma concentrations reached steady-state on Day 3 without relevant accumulation. The geometric mean t½ on Day 8 was 6.0 h. The night-time median time to maximum plasma concentration, geometric mean t½, geometric mean maximum plasma concentration, and area under the curve from zero to 24 h were 1.5 h, 6.1 h, 475 ng/mL, and 3729 ng·h/mL, respectively. No relevant effects on any of the PD variables, neither objective (SPV, adaptive tracking, body sway, DSST, SRTT) nor subjective (VAS Bond and Lader, KSS, LSEQ, VAS Bowdle) were observed. Evening administration of ACT-541468 was well tolerated with no apparent next-day impairment of motor and cognitive functions which supports the further development of ACT-541468 in insomnia disorders. Clemens Muehlan and Jasper Dingemanse are employees at Idorsia, the sponsor of the clinical study. The investigators Joop van Gerven, Rob Zuiker, and Sander Brooks are employees of CHDR. The authors disclosed no other relevant affiliations or financial interest.