Safety, tolerability, and pharmacokinetics of 4-fluoroetomidate (NH600001) in healthy subjects: a first-in-human, randomised, controlled, phase I study.

BACKGROUND

NH600001 (formerly EL-0052) is a novel 4-fluoroetomidate formulated as a lipid emulsion. This first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose trial aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NH600001.

METHODS

Eighty-eight healthy volunteers were randomized into seven dose cohorts (0.04-0.40 mg/kg). Each cohort included NH600001, placebo, and etomidate as an active comparator. The injectable emulsion was administered as a single, 10 mL intravenous dose over one minute using a syringe pump. Safety was assessed by clinical evaluations, laboratory tests, electrocardiography, and treatment-emergent adverse events (TEAEs). Plasma drug concentrations were measured for PK analysis, and bispectral index (BIS), modified observer assessment of alertness/sedation (MOAA/S), and eyelash reflex were used as PD indicators.

RESULTS

Of 88 participants, 58 received NH600001, 16 received etomidate, and 14 received placebo. A total of 57 subjects (64.8 %) reported 130 TEAEs, most of which were mild; no serious adverse events were reported. TEAE incidence was 62.1 % in the NH600001 group, 81.3 % in the etomidate group, and 57.1 % in the placebo group. NH600001 did not induce adrenocortical suppression, in contrast to etomidate. Across the dose groups, the mean time to maximum plasma concentration (Tmax) ranged from 2.5 ± 0.9 to 3.9 ± 3.3 min, while the mean terminal half-life (t1/2) ranged from 4.9 to 38.6 h. A linear dose-exposure relationship was observed for area under the concentration-time curve from zero to infinity (AUC0-∞) and to the last quantifiable concentration (AUC0-t) across 0.04-0.40 mg/kg. At 0.26 mg/kg, NH600001 produced anesthetic onset (1.8 min) and duration (4.9 min) comparable to 0.30 mg/kg etomidate.

CONCLUSIONS

NH600001 demonstrated favorable safety and tolerability, with reduced adrenocortical suppression compared to etomidate. Doses of 0.20-0.30 mg/kg are supported for further clinical development. These findings suggest NH600001 may offer a promising alternative to etomidate by preserving anesthetic efficacy while minimizing endocrine adverse effects.