Pharmacokinetics, safety, and pharmacodynamics of intravenous methoxyethyl etomidate hydrochloride (ET-26-HCl) in Chinese participants with hepatic impairment.

BACKGROUND: Intravenous methoxyethyl etomidate hydrochloride (ET-26-HCl) is a novel etomidate analogue. We aimed to investigate the pharmacokinetics, safety and pharmacodynamics of ET-26-HCl in individuals with hepatic impairment. METHODS: In this open-label, parallel study, we compared the pharmacokinetics, pharmacodynamics and safety of a single intravenous bolus dose of 0.8 mg kg-1 ET-26-HCl for 1 min between patients with mild or moderate hepatic impairment (Child‒Pugh A/B) and those of healthy participants matched for sex, age, and body weight. Each cohort included eight participants. The pharmacokinetics of ET-26-HCl and its predominant metabolite, ET-26-acid, were characterized. Safety was assessed through vital signs, laboratory tests, physical examinations and adverse events (AEs). Pharmacodynamics were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) and the bispectral index (BIS). RESULTS: Twenty-four participants completed the study. Compared with that of healthy participants, the arterial plasma AUC geometric means of ET-26-HCl were similar in patients with a moderate impairment and increased in those with mild impairment. The geometric mean ratios for the venous plasma AUC of ET-26-HCl were ∼1.31- and ∼1.48-fold greater in patients with mild and moderate impairment, respectively, than in healthy participants. Most AEs were mild to moderate. No serious AEs occurred. The degree of hepatic impairment had little effect on the MOAA/S and BIS of ET-26-HCl. CONCLUSION: Venous plasma ET-26-HCl exposure was ∼1.31- and ∼1.48-fold greater in patients with mild and moderate hepatic impairment, respectively, than in matched healthy controls. ET-26-HCl was generally safe and well tolerated by all participants in this study. Importantly, these findings should not be extrapolated to patients with severe hepatic impairment. CLINICAL TRIAL REGISTRATION: NCT06176716, https://clinicaltrials.gov/.