Background

Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation.

Objective

The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant.

Method

This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed.

Results

Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (t_max) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness.

Conclusions

Apart from a shift in t_max, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant.

Clinical Trials Registration number:

NCT03609775 (ClinicalTrials.gov Identifier)

中文翻译：

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在健康受试者的双盲、随机、安慰剂对照、双模拟、四向交叉 I 期研究中，双重食欲素受体拮抗剂 Daridorexant 和乙醇之间的药理学相互作用

背景

Daridorexant (ACT-541468) 是一种有效的双食欲素受体拮抗剂，正在开发中，用于治疗睡眠障碍。已证明同时摄入乙醇和催眠药会导致中枢神经系统的加成/超加成抑制，导致明显的镇静作用。

客观的

本研究的目的是评估乙醇和daridorexant 之间的药代动力学（PK）和药效学（PD）相互作用。

方法

这是一项在 19 名健康男性/女性受试者中进行的单中心、双盲、安慰剂对照、随机、四向交叉研究。受试者接受以下四种治疗：乙醇加daridorexant、单独daridorexant、单独乙醇和安慰剂。Daridorexant 50 mg 和匹配的安慰剂作为单片口服片剂给药。乙醇通过静脉输注并固定在 0.6 g/L 的水平上 5 小时。评估了乙醇和 daridorexant 的 PK 并进行了一系列 PD 测试。

结果

乙醇的伴随给药延长了达瑞多雷克达到最大血浆浓度 ( t _max ) 的时间（中位差为 1.25 小时）。没有观察到其他相关的 PK 相互作用。与单独使用 daridorexant 相比，与乙醇共同给药对扫视峰值速度、身体摇摆、视觉模拟量表 (VAS) 警觉性、VAS 酒精中毒、平稳追踪和适应性跟踪产生了更大的损害。所有治疗通常都具有良好的耐受性，没有严重的不良事件 (AE)。daridorexant 和乙醇共同给药后最常报告的治疗出现的 AE 包括嗜睡、头痛、疲劳、突然入睡和头晕。

结论

除了t _{max 的}变化之外，在daridorexant和乙醇的共同给药后没有观察到PK参数的相关变化。共同给药导致增强的药物作用，最多表明对某些 PD 标志物的红外线加成效应。将建议患者不要与 daridorexant 一起食用乙醇。

临床试验注册号：

NCT03609775（ClinicalTrials.gov 标识符）