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

Abstract

In patients with chronic obstructive pulmonary disease (COPD), sleep is often fragmented while, conversely, the use of sleep medications is of concern in these patients due to potential impairment of nocturnal breathing. This randomised, double‐blind, placebo‐controlled, two‐period crossover study was conducted to evaluate the effect of the new dual orexin receptor antagonist daridorexant on night‐time respiratory function and sleep in patients with moderate COPD. In each period, the highest Phase‐III dose of 50 mg daridorexant or placebo was administered once daily in the evening for 5 consecutive days. The primary endpoint was peripheral oxygen saturation (SpO2) during total sleep time (TST) after last dosing. Night‐time respiratory function and sleep were further evaluated based on the apnea–hypopnea index (AHI), sleep duration, and objective sleep parameters. Pharmacokinetics, safety, and tolerability were also assessed. Primary endpoint analysis revealed no significant mean treatment difference (i.e. daridorexant – placebo) for SpO2 during TST as it was 0.18% (90% confidence interval: −0.21 to 0.57). There was also no difference from placebo for SpO2 during non‐rapid eye movement (REM) and REM sleep at Night 5 and after first dosing. The AHI was slightly increased compared to placebo, but not to a clinically meaningful extent. In addition, daridorexant improved objective sleep parameters (i.e. prolonged TST, increased sleep efficiency, and decreased wake after sleep onset), reached expected plasma concentrations, and was safe and well tolerated. In conclusion, single and multiple doses of 50 mg daridorexant do not impair night‐time respiratory function and improves sleep in patients with moderate COPD.

Daridorexant: First Approval

“…Administration of daridorexant to patients (n = 25) with mild-to-moderate OSA (5-30 apnoea-hypopnoea events/h) not requiring continuous positive airway pressure (CPAP) for 5 days was associated with a 0.74 (90% CI -1.43 to 2.92) events/h mean treatment difference in apnoea/hypopnoea index during total sleep time (TST) compared to placebo [13]. Administration of daridorexant to patients (n = 26) with moderate COPD was not associated with a significant change in peripheral oxygen saturation during TST compared to placebo (mean treatment difference 0.18% (90% CI − 0.21 to 0.57) [14]. However, because of study limitations including small patient numbers and short study durations, and because patients with severe OSA or COPD were not included, the possibility of clinically meaningful respiratory depressant effects occurring during treatment with daridorexant cannot be excluded [5].…”

Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations

“…The effects on respiratory function are also worthy of investigation. 202 In this respect, daridorexant was found not to impair nighttime respiratory function in patients with moderate chronic obstructive pulmonary disease 206 or with mild or moderate OSAS. 207 Moreover, daridorexant does not alter cardiac indexes, such as the QT interval.…”

Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder

“…No PK analyses were performed from this study but within the clinical pharmacology program of daridorexant, the pharmacokinetics/pharmacodynamics of daridorexant has been evaluated in healthy young and older adults [37,38]. Specific safety aspects, including the modulating effects of intrinsic [51] and extrinsic factors [52][53][54], human abuse potential [44] and effects on driving performance [55] and safety in special populations (subjects with respiratory disease [56,57] and hepatic or renal impairment [58,59]) have also been evaluated. To summarise, daridorexant is quickly absorbed and cleared from the plasma and the distinct pharmacodynamic effects observed are in accordance with the pharmacokinetics, i.e.…”