在健康志愿者中进行的1期单中心安慰剂和依托咪酯对照研究，以评估静脉注射盐酸甲氧基乙基依托咪酯（ET-26）的安全性、耐受性、临床效果和药代动力学。

Phase 1 single-centre placebo- and etomidate-controlled study in healthy volunteers to assess safety, tolerability, clinical effects, and pharmacokinetics of intravenous methoxyethyl etomidate hydrochloride (ET-26).

作者信息

Yin Qinqin, Yang Yang, Liu Jin, Li Lize, Yang Xiaoran, Diao Lei, Sun Yi, Zhang Wensheng, Deng Xiaoqian

机构信息

Department of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.

Department of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Laboratory of and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.

出版信息

Br J Anaesth. 2025 Jan;134(1):80-88. doi: 10.1016/j.bja.2024.09.009. Epub 2024 Oct 29.

DOI:10.1016/j.bja.2024.09.009

PMID:39477713

Abstract

BACKGROUND

Methoxyethyl etomidate hydrochloride (ET-26) is a novel etomidate analogue. This is the first-in-human study of a bolus i.v. formulation of ET-26 to assess its safety, tolerability, hypnotic effects, and pharmacokinetics.

METHODS

We enrolled 58 subjects in a dose-escalating study (stage 1a, 10 cohorts, ET-26 0.05-2.8 mg kg) and 40 subjects in a head-to-head study (stage 1b, four cohorts). Safety estimates included vital signs, adverse events, physical examination, and laboratory tests. Hypnotic effects were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale, bispectral index, loss of eyelash reflex, and response to pain. Adrenocortical function was assessed using plasma total cortisol (PTC), and area above the PTC baseline (AUC) after adrenocorticotropic hormone stimulation. Pharmacokinetics of plasma ET-26 concentrations were investigated.

RESULTS

No severe adverse events occurred; the most common adverse events were myoclonus (53.8%) and injection pain (47.4%), which were transient and resolved spontaneously. Vital signs remained stable. ET-26 produced rapid-onset, short-duration unconsciousness. At the 95% effective dose (ED, 0.8 mg kg), ET-26 produced unconsciousness with a similar onset time (1.9 [0.6] min vs 2.1 [1.3] min) and slightly shorter duration (2.9 [0.9] vs 4.8 [1.8]) compared with etomidate 0.3 mg kg, and resulted in higher AUC (614 [454] vs -932 [555] nmol h). ET-26 showed linear pharmacokinetics, and a two-compartment model best described the pharmacokinetics.

CONCLUSIONS

ET-26 was tolerated in healthy volunteers up to 2.8 mg kg. It produced rapid-onset, short-acting unconsciousness with stable cardiovascular and respiratory properties. Adrenocortical function was better preserved compared with etomidate 0.3 mg kg.

CLINICAL TRIAL REGISTRATION

ChiCTR2100047525 (https://www.chictr.org.cn/index.aspx, ChiCTR2100047525).

摘要

背景

盐酸甲氧基乙基依托咪酯（ET - 26）是一种新型依托咪酯类似物。这是首次在人体中对ET - 26静脉推注制剂进行研究，以评估其安全性、耐受性、催眠效果和药代动力学。

方法

我们在剂量递增研究（1a期，10个队列，ET - 26 0.05 - 2.8 mg/kg）中纳入了58名受试者，并在头对头研究（1b期，4个队列）中纳入了40名受试者。安全性评估包括生命体征、不良事件、体格检查和实验室检查。使用改良的观察者警觉/镇静评估量表（MOAA/S）、脑电双频指数、睫毛反射消失和对疼痛的反应来评估催眠效果。使用血浆总皮质醇（PTC）以及促肾上腺皮质激素刺激后PTC基线以上的面积（AUC）来评估肾上腺皮质功能。研究了血浆ET - 26浓度的药代动力学。

结果

未发生严重不良事件；最常见的不良事件是肌阵挛（53.8%）和注射痛（47.4%），均为短暂性且可自发缓解。生命体征保持稳定。ET - 26产生快速起效、持续时间短的意识丧失。在95%有效剂量（ED，0.8 mg/kg）时，与0.3 mg/kg的依托咪酯相比，ET - 26产生意识丧失的起效时间相似（1.9 [0.6]分钟对2.1 [1.3]分钟），持续时间略短（2.9 [0.9]对4.8 [1.8]），且AUC更高（614 [454]对 - 932 [555] nmol·h）。ET - 26显示出线性药代动力学，二室模型最能描述其药代动力学。