Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY; and.
Department of Fundamental Disciplines and Clinical Prevention, Faculty of Medicine, Transilvania University of Brasov, Brasov, Romania.
Am J Ther. 2023;30(4):e360-e368. doi: 10.1097/MJT.0000000000001647.
Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep.
MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted.
The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported.
Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.
失眠是一种常见的睡眠障碍，主要通过患者的主观报告症状来诊断。达力雷汀是一种新的双重食欲素受体拮抗剂，最近被美国食品和药物管理局批准用于入睡困难和/或维持睡眠的失眠症。
作用机制、药效学和药代动力学：食欲素神经肽信号系统在觉醒中起作用，阻断促觉醒神经肽会导致觉醒信号减弱，从而通过与经典的促眠药物完全不同的作用机制产生镇静作用。该药物起效迅速，分布容积大，蛋白结合率高。不同性别和年龄的患者的药代动力学和药效学参数相似，且不受种族、体型或轻度至中度肾功能损害的影响。建议中度肝损伤患者剂量限制在 25mg，严重肝损伤患者禁用。该药物经肝 CYP3A4 代谢；因此，需要谨慎使用强效 CYP3A4 抑制剂和诱导剂。
该药物是基于涉及研究 1 和研究 2 的 3 期试验获得批准的。研究 1 表明，达力雷汀 25mg 和 50mg 剂量在 1 个月和 3 个月时与安慰剂相比，在睡眠后觉醒时间、持续睡眠潜伏期和自我报告的总睡眠时间方面均显示出统计学上的显著改善。同样，在研究 2 中，与安慰剂相比，25mg 剂量在 1 个月和 3 个月时在睡眠后觉醒时间、持续睡眠潜伏期和自我报告的总睡眠时间方面均显示出统计学上的显著改善。达力雷汀和安慰剂的治疗中出现的不良反应相似，最常报告的是鼻咽炎和头痛。
达力雷汀是一种新的药物，在入睡和维持睡眠以及减少白天镇静方面具有疗效。为期 1 年的扩展研究的初步结果表明，其轻度至中度副作用的发生率与之前的试验相似。还需要进一步的研究来确定它在失眠药物治疗中的地位。
