Fan Yang, Pan-Pan Ye, Wen-Shuo Lv, Li-Ze Li, Bao-Zhong Zhao, John van denAnker, Xin-Mei Yang, Lin-Lin Song, Xiao-Ran Yang, Yi Zheng, Bo-Wen Ke, Wei Zhao
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引用次数: 0
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 AUC0-∞ for ET-26 (GMR 90.0%, 90% CI 85.4%-94.8%), while co-administration fluconazole increased the AUC0-∞ by 18.5% (GMR 118.5%, 90% CI 111.4%-126.2%). ET-26 slightly increased the AUC0-∞ 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.
期刊介绍:
The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.