Background and Objectives

Remimazolam is a new ultra-short-acting benzodiazepine currently being developed for intravenous use in procedural sedation, general anaesthesia, and intensive care unit sedation. Benzodiazepines represent a drug class associated with drug-facilitated sexual assaults, especially in combination with alcohol. Two clinical trials were designed to evaluate the oral bioavailability and pharmacokinetics/pharmacodynamics of remimazolam and to assess the potential for remimazolam misuse in drug-facilitated sexual assaults via oral ingestion.

Methods

Trial 1 was conducted in 14 healthy volunteers to evaluate the oral bioavailability of remimazolam. Part 1 of trial 2 was conducted in 21 healthy female volunteers to find the minimal biologically active dose of oral remimazolam. Part 2 of trial 2 was conducted in 11 healthy female volunteers to evaluate the pharmacokinetics/pharmacodynamics of oral remimazolam in combination with alcohol.

Results

Remimazolam undergoes rapid and extensive first-pass metabolism upon oral administration. The oral bioavailability of remimazolam was negligible (2.2% based on total systemic exposure and 1.2% based on maximum plasma concentration). Plasma clearance of both remimazolam and its metabolite was fast (elimination half-life 20‒40 min and 1.75‒2 h, respectively). Alcohol did not appear to inhibit the rapid first-pass metabolism of remimazolam. No clear sedative effects were observed for remimazolam without alcohol. Significant sedation was observed in one of ten subjects after remimazolam 360 mg (18 drug product vials) + 40% v/v alcohol.

Conclusion

The oral bioavailability of remimazolam is negligible, which—together with its distinct bitter taste—suggests no meaningful potential for misuse in drug-facilitated sexual assaults via oral ingestion, with or without alcohol.

Clinical Trial Registration Numbers

Trial 1 (NCT04113564) and trial 2 (NCT04113343) both retrospectively registered on 2 October 2019.

中文翻译：

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Remimazolam 的口服生物利用度低，在有或没有酒精的情况下，在药物促进的性侵犯中没有滥用的可能性：两项随机临床试验的结果。

背景和目标

Remimazolam 是一种新的超短效苯二氮卓类药物，目前正在开发中用于程序镇静、全身麻醉和重症监护室镇静的静脉注射。苯二氮卓类药物代表与药物促成的性侵犯相关的一类药物，特别是与酒精结合使用。设计了两项临床试验以评估瑞马唑仑的口服生物利用度和药代动力学/药效学，并评估瑞马唑仑在通过口服摄入药物促成的性侵犯中滥用的可能性。

方法

试验 1 在 14 名健康志愿者中进行，以评估瑞马唑仑的口服生物利用度。试验 2 的第 1 部分在 21 名健康女性志愿者中进行，以找到口服 remimazolam 的最小生物活性剂量。试验 2 的第 2 部分在 11 名健康女性志愿者中进行，以评估口服 remimazolam 与酒精联合的药代动力学/药效学。

结果

Remimazolam 在口服给药时经历快速和广泛的首过代谢。瑞马唑仑的口服生物利用度可以忽略不计（基于全身总暴露量为 2.2%，基于最大血浆浓度为 1.2%）。瑞马唑仑及其代谢物的血浆清除速度很快（消除半衰期分别为 20-40 分钟和 1.75-2 小时）。酒精似乎不会抑制瑞马唑仑的快速首过代谢。没有观察到没有酒精的瑞马唑仑有明显的镇静作用。在 remimazolam 360 mg（18 个药品瓶）+ 40% v/v 酒精后，10 名受试者中的一名观察到明显的镇静作用。

结论

remimazolam 的口服生物利用度可以忽略不计，再加上其独特的苦味，这表明在有或没有酒精的情况下通过口服摄入药物促成的性侵犯中没有有意义的滥用潜力。

临床试验注册号

试验 1 (NCT04113564) 和试验 2 (NCT04113343) 均于 2019 年 10 月 2 日追溯注册。