Anesthesiology. 2020 Dec 1;133(6):1192-1213. doi: 10.1097/ALN.0000000000003577.
Several models describing the pharmacokinetics of ketamine are published with differences in model structure and complexity. A systematic review of the literature was performed, as well as a meta-analysis of pharmacokinetic data and construction of a pharmacokinetic model from raw data sets to qualitatively and quantitatively evaluate existing ketamine pharmacokinetic models and construct a general ketamine pharmacokinetic model.
Extracted pharmacokinetic parameters from the literature (volume of distribution and clearance) were standardized to allow comparison among studies. A meta-analysis was performed on studies that performed a mixed-effect analysis to calculate weighted mean parameter values and a meta-regression analysis to determine the influence of covariates on parameter values. A pharmacokinetic population model derived from a subset of raw data sets was constructed and compared with the meta-analytical analysis.
The meta-analysis was performed on 18 studies (11 conducted in healthy adults, 3 in adult patients, and 5 in pediatric patients). Weighted mean volume of distribution was 252 l/70 kg (95% CI, 200 to 304 l/70 kg). Weighted mean clearance was 79 l/h (at 70 kg; 95% CI, 69 to 90 l/h at 70 kg). No effect of covariates was observed; simulations showed that models based on venous sampling showed substantially higher context-sensitive half-times than those based on arterial sampling. The pharmacokinetic model created from 14 raw data sets consisted of one central arterial compartment with two peripheral compartments linked to two venous delay compartments. Simulations showed that the output of the raw data pharmacokinetic analysis and the meta-analysis were comparable.
A meta-analytical analysis of ketamine pharmacokinetics was successfully completed despite large heterogeneity in study characteristics. Differences in output of the meta-analytical approach and a combined analysis of 14 raw data sets were small, indicative that the meta-analytical approach gives a clinically applicable approximation of ketamine population parameter estimates and may be used when no raw data sets are available.
有几个描述氯胺酮药代动力学的模型已经发表，这些模型在结构和复杂性上存在差异。我们进行了文献综述，并对药代动力学数据进行了荟萃分析，从原始数据集构建药代动力学模型，以定性和定量评估现有的氯胺酮药代动力学模型，并构建一般的氯胺酮药代动力学模型。
从文献中提取药代动力学参数（分布容积和清除率），并进行标准化，以便在研究之间进行比较。对进行混合效应分析以计算加权平均参数值的研究进行荟萃分析，并进行荟萃回归分析以确定协变量对参数值的影响。从原始数据集的子集构建药代动力学群体模型，并与荟萃分析进行比较。
对 18 项研究（11 项在健康成年人中进行，3 项在成年患者中进行，5 项在儿科患者中进行）进行了荟萃分析。加权平均分布容积为 252 l/70 kg（95% CI，200 至 304 l/70 kg）。加权平均清除率为 79 l/h（在 70 kg 时；95% CI，70 kg 时 69 至 90 l/h）。未观察到协变量的影响；模拟表明，基于静脉采样的模型显示出的上下文敏感半衰期明显高于基于动脉采样的模型。从 14 个原始数据集构建的药代动力学模型由一个中央动脉隔室和两个与两个静脉延迟隔室相连的外周隔室组成。模拟表明，原始数据药代动力学分析和荟萃分析的输出结果相当。
尽管研究特征存在很大异质性，但氯胺酮药代动力学的荟萃分析成功完成。荟萃分析方法的输出结果与 14 个原始数据集的综合分析结果差异较小，表明荟萃分析方法可提供氯胺酮群体参数估计的临床适用近似值，并且在没有原始数据集时可以使用。
