0377 Clinical Pharmacology Of The Dual Orexin Receptor Antagonist Act-541468 In Elderly Subjects

Abstract

Introduction: The orexin system regulates sleep and arousal. Following single‐ascending dose (SAD) morning and repeated evening administration of ACT‐541468, pharmacokinetics (PK), pharmacodynamics (PD), safety, tolerability, and residual next‐day effects were investigated in healthy elderly subjects. Methods: Double‐blind, placebo‐controlled, randomized, SAD study (5, 15, and 25 mg in the morning) in 24 male and female elderly subjects (65‐80 years, 6/2 active/placebo per group, 1:1 sex ratio). In a separate study part, 10 subjects (8/2 active/placebo) received 25 mg for 7 days at bedtime. PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analog scales, Karolinska Sleepiness Scale), safety, and tolerability were assessed. Results: Absorption of ACT‐541468 was quick, with median maximum plasma concentrations reached at 0.8‐1.0 h across the dose range. The geometric mean elimination half‐life was 8.5‐9.8 h, the area under the curve, and the maximum plasma concentration increased proportionally to the dose administered. Following evening administration of 25 mg for 7 days, no relevant accumulation was observed. In the SAD part, there were no PD effects at 5 mg. At 15 mg, SPV was reduced, returning to baseline after 12 h, while other PD variables showed no effects. At 25 mg, effects on all PD parameters were observed, with an onset ≤ 1 h postdose and a maximum mean effect at 1‐2 h. PD effects returned to baseline 8‐12 h post‐dose. No next‐day residual effects on objective and subjective PD variables were observed when assessments were performed in the next morning after evening administration. The incidence of adverse events in the elderly subjects of this study was lower when compared to young adults in previous studies. Conclusion: ACT‐541468 in elderly subjects, both after morning and evening administration, was safe and PK and PD are compatible with a drug for the treatment of insomnia.