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-1) 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 (AUCPTC) 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 (ED95, 0.8 mg kg-1), 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-1, and resulted in higher AUCPTC (614 [454] vs -932 [555] nmol h-1). 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-1. 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-1. CLINICAL TRIAL REGISTRATION ChiCTR2100047525 (https://www.chictr.org.cn/index.aspx, ChiCTR2100047525).

中文翻译：

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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酯依托咪酯 （ET-26） 的安全性、耐受性、临床效果和药代动力学。


背景 盐酸甲氧基乙酯依托咪酯 （ET-26） 是一种新型依托咪酯类似物。这是 ET-26 推注静脉注射制剂的首次人体研究，以评估其安全性、耐受性、催眠作用和药代动力学。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-1） 中招募了 58 名受试者，在头对头研究中招募了 40 名受试者 （1b 期，四个队列）。安全性估计包括生命体征、不良事件、体格检查和实验室检查。使用改良观察者警觉性/镇静评估 （MOAA/S） 量表、双频指数、睫毛反射丧失和对疼痛的反应评估催眠效果。使用血浆总皮质醇 （PTC） 和促肾上腺皮质激素刺激后 PTC 基线以上面积 （AUCPTC） 评估肾上腺皮质功能。研究血浆 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%），它们是短暂的并自发消退。生命体征保持稳定。ET-26 产生快速发作、短时间的昏迷。在 95% 有效剂量 （ED95， 0.8 mg kg-1） 下，ET-26 产生昏迷，与依托咪酯 0.3 mg kg-1 相比，具有相似的起效时间 （1.9 [0.6] 分钟 vs 2.1 [1.3] 分钟） 和略短的持续时间 （2.9 [0.9] vs 4.8 [1.8]），并导致更高的 AUCPTC （614 [454] vs -932 [555] nmol h-1）。ET-26 显示出线性药代动力学，两室模型最能描述药代动力学。结论 ET-26 在健康志愿者中耐受高达 2.8 mg kg-1。它产生快速发作的短效无意识，具有稳定的心血管和呼吸特性。 与依托咪酯 0.3 mg kg-1 相比，肾上腺皮质功能保存得更好。临床试验注册 ChiCTR2100047525 （https://www.chictr.org.cn/index.aspx， ChiCTR2100047525）。