Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration

Abstract

Background: The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. Methods: Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65–80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. Results: Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5–9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8–12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. Conclusion: ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855

Effect of the novel dual orexin receptor antagonist daridorexant on night‐time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease

“…In the present study, daridorexant was safe and well tolerated at the dose of 50 mg based on AE and other safety data, suggesting that daridorexant does not worsen the disease condition in patients with moderate COPD. Except for one AE of fatigue, none of the reported AEs was suggestive of next‐day residual effect of daridorexant, consistent with previous studies in healthy subjects (Muehlan, Boehler, et al., 2020; Muehlan et al., 2018, 2019; Muehlan, Zuiker, et al., 2020) and patients with insomnia (Dauvilliers et al., 2020; Zammit et al., 2020).…”

“…Daridorexant and placebo were orally administered at night‐time for 5 consecutive days. The 5‐day exposure duration was considered sufficient, as steady state exposure of daridorexant and its metabolites is reached after 3 days without relevant accumulation, as previously determined in healthy subjects (Muehlan, Boehler, et al., 2020; Muehlan et al., 2019; Muehlan, Zuiker, et al., 2020). Both study periods were separated by a washout period lasting 1–2 weeks.…”

“…Phase II studies in adults and elderly patients with insomnia demonstrated that daridorexant dose‐dependently reduced wake after sleep onset (WASO) and latency to persistent sleep (LPS) (Dauvilliers et al., 2020; Zammit et al., 2020). After multiple dosing, an overall favourable safety and tolerability profile was observed after daridorexant administration in both healthy subjects (up to 75 mg) and patients with insomnia (up to 50 mg) (Dauvilliers et al., 2020; Muehlan, Boehler, et al., 2020; Muehlan et al., 2019; Muehlan, Zuiker, et al, 2020; Zammit et al., 2020).…”

Pharmacokinetics of daridorexant, a dual orexin receptor antagonist, are not affected by renal impairment

“…In the present study, the safety profile of daridorexant was similar to previous observations. 5,8,[11][12][13]20 Administration of daridorexant was well tolerated in all individuals and no safety concern related to the administration of daridorexant was raised.…”

“…PK results in control subjects in this study were within the range of variability observed in other studies, in which a single oral dose of 25 mg daridorexant was administered to a similarly aged population. 11 , 12 , 20 An apparent explanation for the outlier in group A could not be determined as nothing out of the ordinary in terms of demographic characteristics, medical history, and clinical laboratory variables was evident, whereas there was no concomitant intake of other drugs. The inherent variability of expression and function of CYP3A4, both intra‐ and interindividually, is considered a possible explanation.…”