Etomidate analogue promising agent for general anesthesia induction with rapid recovery profile: Study

Recently published study focused on the evaluation of a novel etomidate analogue, methoxyethyl etomidate hydrochloride (ET-26), in healthy volunteers to assess its safety, tolerability, hypnotic effects, and pharmacokinetics. Etomidate, an intravenous general anesthetic, is known for cardiovascular stability but has limitations such as adrenocortical suppression. Efforts have been made to develop etomidate analogues that preserve its benefits while addressing its drawbacks. ET-26 was designed to maintain anesthesia properties while reducing adrenocortical suppression through a modified ester side chain.

Phase 1 Clinical Trial of ET-26

The study, a phase 1 single-center trial, included two stages: a dose-escalation study (stage 1a) and a head-to-head study (stage 1b) comparing ET-26 with etomidate. The primary endpoints were safety and tolerability, while secondary endpoints included pharmacokinetic and pharmacodynamic properties. Healthy participants aged 18-45 were enrolled, and ET-26 was administered intravenously at escalating doses.

Safety and Tolerability of ET-26

Safety assessments revealed that ET-26 was well-tolerated, with dose-dependent hypnotic effects observed. Adverse events were mainly mild, including bradycardia, myoclonus, and injection site pain. Hypnotic effects were dose-dependent, with ET-26 producing rapid-onset and short-lasting unconsciousness. The onset time and duration of unconsciousness increased with higher doses. ET-26 exhibited a more favorable adrenocortical response compared to etomidate, with less suppression observed. Pharmacokinetic evaluations showed a linear profile for ET-26, fitting a two-compartment model. Plasma concentrations of ET-26 and its major metabolite increased with dose escalation. The study also evaluated the dose-effect relationship, indicating increasing incidence of sedation, unconsciousness, and adrenal insufficiency with higher doses of ET-26. The recommended dose for unconsciousness was determined to be 0.8 mg/kg, with a maximum tolerable dose of 2.8 mg/kg.

Promising Aspects of ET-26

The results highlighted ET-26 as a promising agent for general anesthesia induction, with a wide therapeutic window and rapid recovery profile. The analogue demonstrated better adrenocortical function preservation compared to etomidate, with a more favorable pharmacokinetic profile. Myoclonus observed with ET-26 was transient and spontaneously resolved, distinguishing it from the involuntary muscle movements associated with etomidate analogues like ABP-700. The study provided valuable insights into the safety, clinical effects, and pharmacokinetics of ET-26 in healthy volunteers, suggesting its potential as a novel anesthetic agent with improved safety profile and hypnotic efficacy.

Key Points

- Evaluation focused on a novel etomidate analogue, ET-26, designed to maintain anesthesia properties while reducing adrenocortical suppression through a modified ester side chain.

- Phase 1 clinical trial of ET-26, a single-center trial including dose-escalation and head-to-head studies with etomidate, showed well-tolerated, dose-dependent hypnotic effects with mild adverse events such as bradycardia, myoclonus, and injection site pain.

- Safety and tolerability assessments revealed ET-26 produced rapid-onset and short-lasting unconsciousness in a dose-dependent manner, with a more favorable adrenocortical response compared to etomidate.

- Pharmacokinetic evaluations showed linear profile and two-compartment model fitting for ET-26, with plasma concentrations and metabolite levels increasing with dose escalation, determining a recommended dose of 0.8 mg/kg for unconsciousness and maximum tolerable dose of 2.8 mg/kg.

- Promising aspects of ET-26 include wide therapeutic window and rapid recovery profile for general anesthesia induction, better preservation of adrenocortical function, and transient myoclonus with spontaneous resolution, suggesting potential as a novel anesthetic agent with improved safety and hypnotic efficacy.

- Study provides insights into safety, clinical effects, and pharmacokinetics of ET-26 in healthy volunteers, indicating its potential as a safer and more effective alternative to etomidate for general anesthesia induction.

Reference –

J. Sneyd & Beatrijs I. Valk (2024). Etomidate And Its Derivatives: Time To Say Goodbye?. *British Journal Of Anaesthesia*, 134 1, 11-13 . https://doi.org/10.1016/j.bja.2024.09.011.