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

IF 2.9 4区 医学
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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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.

甲氧乙基依托咪酯盐酸盐(ET-26):一项评估健康受试者药物相互作用的I期临床试验
甲氧乙基依托咪酯盐酸盐(ET-26)是一种新型静脉全身麻醉剂,旨在解决依托咪酯的临床局限性。本I期临床试验评估了ET-26在68名健康受试者中的药代动力学、药效学、药物-药物相互作用(DDI)潜力和安全性,评估了ET-26与利福平(CYP2C19/3A4诱导剂)、氟康唑(CYP2C19/3A4抑制剂)和奥美拉唑/咪达唑仑的相互作用。ET-26药代动力学分析显示,与单独给药ET-26相比,利福平联合给药可使ET-26的AUC0-∞几何平均比值(GMR)降低10% (GMR 90.0%, 90% CI 85.4% ~ 94.8%),而氟康唑联合给药可使ET-26的AUC0-∞几何平均比值(GMR 118.5%, 90% CI 111.4% ~ 126.2%)升高18.5% (GMR 118.5%, 90% CI 111.4% ~ 126.2%)。ET-26略微增加奥美拉唑的AUC0-∞18.5% (GMR为118.5%,90% CI为111.4%-126.1%)和咪达唑仑的AUC0-∞11.1% (GMR为111.1%,90% CI为104.9%-117.8%)。关键参数的90% CI基本上落在无影响边界内,表明没有临床显著的ddi。药效学评估显示,不同序列的镇静特征一致,与咪达唑仑有轻微的叠加效应。安全性评估确定了治疗中出现的不良事件,如注射部位疼痛和肌阵挛,氟康唑更常见。未观察到严重不良事件。这些研究结果表明,ET-26具有良好的安全性和药代动力学特征,在临床中没有观察到明显的ddi,支持其作为全身麻醉中依托咪酯更安全的替代品的潜力。
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来源期刊
Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
自引率
3.40%
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0
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.
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