Drugs in R&D · 2025
Pharmacokinetics, Pharmacodynamics, and Safety of ET-26 in Subjects with Mild to Moderate Renal Impairment.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Yang Fan, Shen Chao-Zhuang, Ye Pan-Pan, Lv Wen-Shuo, Li Li-Ze, Shao Jie, Diao Lei, Ke Bo-Wen, Zheng Yi, Yang Xiao-Ran, Zhao Wei
Аннотация
BACKGROUND AND OBJECTIVES: ET-26 is a novel etomidate analog with reduced adrenal suppression. This study evaluated its pharmacokinetics (PK), pharmacodynamics (PD), and safety in subjects with mild to moderate renal impairment.
METHODS: In this phase I trial, 24 subjects (normal renal function, mild renal impairment, moderate renal impairment; n = 8/group) received a single intravenous bolus ET-26 dose. PK parameters (Cmax, AUC0-∞, CL), urinary excretion, PD (time to unconsciousness, area under the curve [AUC] of the Bispectral Index [BIS]), and safety were assessed.
RESULTS: Systemic exposure (AUC0-∞) differed by < 16% between renal impairment and normal groups (geometric mean ratios: 84.70-86.85%). Cmax was ~ 46% lower in renal impairment groups, but PD responses were comparable. Renal clearance was minimal (CLr ≤ 0.0085 L/h; urinary excretion ≤ 0.02%) with no correlation between estimated glomerular filtration rate (eGFR) and PK parameters. Safety profiles were similar across groups; mild myoclonus (25% per cohort) was the most common adverse event. No renal impairment-specific safety concerns emerged.
CONCLUSION: Mild-to-moderate renal impairment minimally affects ET-26 exposure or efficacy due to predominant non-renal elimination. No dosage adjustment is needed for ET-26 0.8 mg/kg in these patients. However, patients with severe renal impairment or those receiving dialysis were not studied, and dedicated investigations are required before extrapolating dosing recommendations to these populations.
TRIAL REGISTRATION: CDE Clinical Trial Registry CTR20233783. Registered on 23 November 2023. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.
METHODS: In this phase I trial, 24 subjects (normal renal function, mild renal impairment, moderate renal impairment; n = 8/group) received a single intravenous bolus ET-26 dose. PK parameters (Cmax, AUC0-∞, CL), urinary excretion, PD (time to unconsciousness, area under the curve [AUC] of the Bispectral Index [BIS]), and safety were assessed.
RESULTS: Systemic exposure (AUC0-∞) differed by < 16% between renal impairment and normal groups (geometric mean ratios: 84.70-86.85%). Cmax was ~ 46% lower in renal impairment groups, but PD responses were comparable. Renal clearance was minimal (CLr ≤ 0.0085 L/h; urinary excretion ≤ 0.02%) with no correlation between estimated glomerular filtration rate (eGFR) and PK parameters. Safety profiles were similar across groups; mild myoclonus (25% per cohort) was the most common adverse event. No renal impairment-specific safety concerns emerged.
CONCLUSION: Mild-to-moderate renal impairment minimally affects ET-26 exposure or efficacy due to predominant non-renal elimination. No dosage adjustment is needed for ET-26 0.8 mg/kg in these patients. However, patients with severe renal impairment or those receiving dialysis were not studied, and dedicated investigations are required before extrapolating dosing recommendations to these populations.
TRIAL REGISTRATION: CDE Clinical Trial Registry CTR20233783. Registered on 23 November 2023. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.