【罂粟摘要】肝、肾功能损害患者使用瑞马唑仑的药代动力学特征
肝、肾功能损害患者使用瑞马唑仑的药代动力学特征
贵州医科大学 高鸿教授课题组
翻译：吴学艳 编辑：佟睿 审校：曹莹
瑞马唑仑是一种新型苯二氮卓类药物，用于程序镇静和全身麻醉，本研究目的是探讨肾、肝受损患者使用瑞马唑仑的药代动力学特征和安全性。
在11例肝功能损害患者与9例匹配的健康受试者(n=11)和11例肾功能损害患者与12例匹配的健康受试者中进行两项独立试验。肝功能损害试验是一项开放标签适应性“减量设计”试验，单次静脉注射0.1mg/kg瑞马唑仑，肾功能损害患者使用单次静脉1.5 mg注射瑞马唑仑的开放试验。通过群体药代动力学模型进行分析瑞马唑仑血浆药物浓度随时间变化的情况。
瑞马唑仑的药代动力学特性符合三室循环模型，与健康自愿者相比，严重肝功能损害受试者的暴露水平升高38.1%(即清除率低38.1%)；引起轻微的恢复延迟(健康患者为8.0分钟，中度肝功能损害患者为12.1分钟，重度肝功能损害患者为16.7分钟)。肾功能受损时，血浆清除率与健康受试者相当，模拟血药峰浓度(Cmax)显示静脉给予大剂量瑞马唑仑10mg后无相关肝脏或肾脏功能损害；不良事件总发生率较低，均为轻微不良事件。
静脉注射瑞马唑仑的Cmax不受肝脏或肾脏功能损害的影响，因此不需要调整剂量，在肝、肾功能受损的受试者中未见与瑞马唑仑相关的不良事件。
原始文献来源：
Stöhr T, Colin PJ, Ossig J, et al. Pharmacokinetic properties of remimazolam in subjects with hepaticor renal impairment[J]. Br J Anaesth. 2021 Jul 8:S0007-0912(21)00346-9. DOI:10.1016/j.bja.2021.05.027. Epub ahead of print.
Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment
Background: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects.
Methods: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design’ trial, using a single bolus of remimazolam 0.1 mg kg-1i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling.
Results: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of Cmaxafter a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild.
Conclusions: As Cmaxafter a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment.