Chen Yueting, Gong Cansheng, Liu Feng, Jiao Zheng, Zheng Xiaochun
Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, China.
Pharmaceutics. 2024 Aug 26;16(9):1122. doi: 10.3390/pharmaceutics16091122.
Remimazolam, widely used for procedural sedation and general anesthesia, is a new ultra short-acting benzodiazepine for intravenous sedation and anesthesia. We aim to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of remimazolam and its metabolite CNS 7054 in healthy Chinese volunteers using population analysis and suggest an optimal dosing regimen for sedation therapy. Data were collected from a single-center, placebo-controlled, randomized, and dose-escalation clinical pharmacology study. Forty-six healthy volunteers received a single infusion dose of remimazolam, while nine healthy subjects received a continuous infusion of remimazolam. A population PK/PD model was established and RxODE and Shiny in R were used to design the remimazolam dosing regimens. A three-compartment model best described the PK of remimazolam and a two-compartment model with one transit compartment was adopted for CNS 7054. The relationship between exposure and the bispectral index was best described using an effect compartment model with an inhibitory sigmoid model. Additionally, a web-based dashboard was developed to provide individualized dosing regimens, complemented by a graphical illustration of the PK/PD profiles of the proposed dosing regimen. The established population PK/PD model characterized the dose-exposure-response relationship of remimazolam well, which could be applied to optimize individual dosing regimens.
瑞马唑仑是一种新型超短效苯二氮䓬类静脉镇静和麻醉药物，广泛用于程序性镇静和全身麻醉。我们旨在通过群体分析来描述瑞马唑仑及其代谢产物CNS 7054在健康中国志愿者体内的药代动力学/药效学（PK/PD）特征，并为镇静治疗推荐最佳给药方案。数据来自一项单中心、安慰剂对照、随机、剂量递增的临床药理学研究。46名健康志愿者接受了单次静脉输注瑞马唑仑，9名健康受试者接受了瑞马唑仑持续输注。建立了群体PK/PD模型，并使用R语言中的RxODE和Shiny来设计瑞马唑仑给药方案。三室模型能最好地描述瑞马唑仑的药代动力学，CNS 7054采用带有一个转运室的二室模型。使用带有抑制性S型模型的效应室模型能最好地描述暴露与脑电双频指数之间的关系。此外，还开发了一个基于网络的仪表盘，以提供个体化给药方案，并辅以所提出给药方案的PK/PD曲线的图形说明。所建立的群体PK/PD模型很好地描述了瑞马唑仑的剂量-暴露-反应关系，可用于优化个体化给药方案。
