Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
Shanghai Qiangshi Information Technology Co., Ltd, Shanghai 201120, China.
J Clin Anesth. 2024 Feb;92:111317. doi: 10.1016/j.jclinane.2023.111317. Epub 2023 Nov 15.
This study aimed to establish a population pharmacokinetic and pharmacodynamic (PK-PD) model to explore the optimal maintenance dose and appropriate starting time of maintenance dose after induction of ciprofol and investigate the efficacy and safety of ciprofol for general anesthesia induction and maintenance in patients undergoing elective surgery.
A total of 334 subjects with 3092 concentration measurements from nine clinical trials and 115 subjects with 5640 bispectral index (BIS) measurements from two clinical trials were used in the population PK-PD analysis. Exposure-response relationships for both efficacy endpoints (duration of anesthesia successful induction, time to recovery from anesthesia, time to respiratory recovery, and time from discontinuation to the 1st/3rd consecutive Aldrete score ≥ 9) and safety variables (hypotension, bradycardia, and injection site pain) were evaluated based on the data gathered from 115 subjects in two clinical trials.
Ciprofol pharmacokinetics (PK) were adequately described by a three-compartment model with first-order elimination from the central compartment and redistribution from the deep and shallow peripheral compartments. An inhibitory sigmoidal Emax model best described the relationship between ciprofol effect-site concentrations and BIS measurements. Body weight, age, sex, blood sampling site, and study type (short-term infusion vs long-term infusion) were identified as statistically significant covariates on the PK of ciprofol. No covariates were found to have a significant effect on the pharmacodynamic (PD) parameters. The PK-PD simulation results showed that the optimal maintenance dose was 0.8 mg/kg/h and the appropriate time to start the maintenance dose was 4-5 mins after the induction dose of ciprofol. Within the exposure range of this study, no meaningful correlations between ciprofol exposures and efficacy or safety endpoints were observed.
A population PK-PD model was successfully developed to describe the ciprofol PK and BIS changes. Efficacy was consistent across the exposure range with a well-tolerated safety profile indicating no maintenance dose adjustment is required for patients undergoing elective surgery.
本研究旨在建立群体药代动力学和药效学（PK-PD）模型，以探讨西普罗诱导后维持剂量的最佳维持剂量和适当起始时间，并探讨西普罗在择期手术患者全身麻醉诱导和维持中的疗效和安全性。
共纳入来自 9 项临床试验的 334 例患者（3092 个浓度测量值）和来自 2 项临床试验的 115 例患者（5640 个脑电双频指数（BIS）测量值）进行群体 PK-PD 分析。根据来自 2 项临床试验的 115 例患者的数据，评估了疗效终点（麻醉诱导成功持续时间、麻醉恢复时间、呼吸恢复时间以及从停药到第 1/3 次连续 Aldrete 评分≥9 的时间）和安全性变量（低血压、心动过缓和注射部位疼痛）的暴露-反应关系。
西普罗药代动力学（PK）通过一个三房室模型得到很好的描述，该模型从中央房室以一级消除，从深部和浅部周围房室重新分布。西普罗效应部位浓度与 BIS 测量值之间的关系最好用抑制性 sigmoidal Emax 模型来描述。体重、年龄、性别、采血部位和研究类型（短期输注与长期输注）被确定为西普罗 PK 的统计学显著协变量。未发现药代动力学参数有显著影响的药效学（PD）参数。PK-PD 模拟结果表明，最佳维持剂量为 0.8mg/kg/h，西普罗诱导剂量后 4-5 分钟开始维持剂量较为合适。在本研究的暴露范围内，西普罗暴露与疗效或安全性终点之间没有明显的相关性。
成功建立了描述西普罗 PK 和 BIS 变化的群体 PK-PD 模型。在可耐受的安全性范围内，疗效在暴露范围内一致，表明无需调整择期手术患者的维持剂量。
