Methoxyethyl Etomidate Hydrochloride (ET-26): A Phase I Clinical Trial Assessing Drug-Drug Interactions in Healthy...

Methoxyethyl etomidate hydrochloride (ET-26) is a novel intravenous general anesthetic designed to address the clinical limitations of etomidate. This Phase I clinical trial assessed the pharmacokinetics, pharmacodynamics, drug-drug interaction (DDI) potential, and safety of ET-26 in 68 healthy subjects across three sequences, evaluating interactions with rifampin (CYP2C19/3A4 inducer), fluconazole (CYP2C19/3A4 inhibitor), and omeprazole/midazolam. ET-26 pharmacokinetic analyses showed that compared with administration of ET-26 alone, co-administration of rifampin resulted in a 10% decrease in the geometric mean ratio (GMR) of the AUC_0-∞ for ET-26 (GMR 90.0%, 90% CI 85.4%-94.8%), while co-administration fluconazole increased the AUC_0-∞ by 18.5% (GMR 118.5%, 90% CI 111.4%-126.2%). ET-26 slightly increased the AUC_0-∞ by 18.5% for omeprazole (GMR 118.5%, 90% CI 111.4%-126.1%) and 11.1% for midazolam (GMR 111.1%, 90% CI 104.9%-117.8%). The 90% CI for key parameters largely fell within no-effect boundaries, indicating no clinically significant DDIs. Pharmacodynamic assessments showed consistent sedation profiles across sequences, with mild additive effects with midazolam. Safety evaluations identified treatment-emergent adverse events such as injection site pain and myoclonus, more frequent with fluconazole. No serious adverse events were observed. These findings suggest ET-26 exhibits a favorable safety and pharmacokinetic profile with no significant DDIs observed in clinical, supporting its potential as a safer alternative to etomidate for general anesthesia.