• Qinqin Yin, Yang Yang, Jin Liu, Lize Li, Xiaoran Yang, Lei Diao, Yi Sun, Wensheng Zhang, and Xiaoqian Deng.
• Department of Anaesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
• Br J Anaesth. 2024 Oct 29.

BackgroundMethoxyethyl 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.MethodsWe 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.ResultsNo 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.ConclusionsET-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 RegistrationChiCTR2100047525 (https://www.chictr.org.cn/index.aspx, ChiCTR2100047525).Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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