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

Fan Yang, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Pan-Pan Ye, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Wen-Shuo Lv, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Li-Ze Li, Avanc Pharmaceutical Co., Ltd., Jinzhou, Liaoning, China.
Bao-Zhong Zhao, Avanc Pharmaceutical Co., Ltd., Jinzhou, Liaoning, China.
John van denAnker, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Xin-Mei Yang, Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China.
Lin-Lin Song, Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China.
Xiao-Ran Yang, Avanc Pharmaceutical Co., Ltd., Jinzhou, Liaoning, China.
Yi Zheng, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Bo-Wen Ke, Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
Wei Zhao, Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

Document Type

Journal Article

Publication Date

7-3-2025

Journal

Journal of clinical pharmacology

DOI

10.1002/jcph.70071

Keywords

Phase 1 clinical trial; drug–drug interaction; etomidate analogs; intravenous anesthetic; pharmacokinetics

Abstract

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 for ET-26 (GMR 90.0%, 90% CI 85.4%-94.8%), while co-administration fluconazole increased the AUC by 18.5% (GMR 118.5%, 90% CI 111.4%-126.2%). ET-26 slightly increased the AUC 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.

Department

Pediatrics

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