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).

Abstract

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. 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 (AUC_PTC) after adrenocorticotropic hormone stimulation. Pharmacokinetics of plasma ET-26 concentrations were investigated. 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 AUC_PTC (614 [454] vs -932 [555] nmol h^-1). ET-26 showed linear pharmacokinetics, and a two-compartment model best described the pharmacokinetics. 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. ChiCTR2100047525 (https://www.chictr.org.cn/index.aspx, ChiCTR2100047525).