From the Department of Anaesthesiology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Servicio de Anestesia, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
Anesth Analg. 2018 Oct;127(4):865-872. doi: 10.1213/ANE.0000000000002814.
The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models.
In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration-bispectral index (BIS) data. Population modeling analysis was performed by nonlinear mixed effects regression in NONMEM (ICON, Dublin, Ireland). PK data from 3 previous studies in obese adult patients (n = 47), including PD (BIS) data from 1 of these studies (n = 20), were pooled and simultaneously analyzed. A decrease in NONMEM objective function (ΔOBJ) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. In the second step of the study, we analyzed the predictive performance (median predictive errors [MDPE] and median absolute predictive errors [MDAPE]) of the current model and of other available models using an independent data set (n = 14).
Step 1: The selected PKPD model produced an adequate fit of the data. Total body weight resulted in the best size scalar for volumes and clearances (ΔOBJ, -18.173). Empirical allometric total body weight relationships did not improve model fit (ΔOBJ, 0.309). A lag time parameter for BIS response improved the fit (ΔOBJ, 89.593). No effect of age or gender was observed. Step 2: Current model MDPE and MDAPE were 11.5% (3.7-25.0) and 26.8% (20.7-32.6) in the PK part and 0.4% (-10.39 to 3.85) and 11.9% (20.7-32.6) in the PD part. The PK model developed by Eleveld et al resulted in the lowest PK predictive errors (MDPE = <10% and MDAPE = <25%).
We derived and validated a propofol PKPD model to perform effect-site TCI in obese patients. This model, derived exclusively from obese patient's data, is not recommended for TCI in lean patients because it carries the risk of underdosing.
本研究旨在推导出一种丙泊酚药代动力学（PK）药效动力学（PD）模型，以便在肥胖患者中进行效应部位靶控输注（TCI），并分析其性能与其他可用 PK 模型的性能。
在研究的第一步中，使用 3 室 PK 模型，通过一阶速率常数（keo）连接到一个 sigmoidal 抑制 Emax PD 模型，以拟合丙泊酚浓度-双谱指数（BIS）数据。通过 NONMEM（爱尔兰都柏林的 ICON）中的非线性混合效应回归进行群体建模分析。对来自 3 项先前肥胖成年患者研究（n = 47）的 PK 数据（包括来自其中 1 项研究（n = 20）的 PD（BIS）数据）进行汇总并同时分析。对于附加参数，NONMEM 目标函数（ΔOBJ）降低 3.84 分被认为具有统计学意义（0.05 水平）。在研究的第二步中，我们使用独立数据集（n = 14）分析了当前模型和其他可用模型的预测性能（中位数预测误差 [MDPE]和中位数绝对预测误差 [MDAPE]）。
步骤 1：所选 PKPD 模型对数据具有良好的拟合度。总体体重导致体积和清除率的最佳大小标度（ΔOBJ，-18.173）。经验性的全部体重比例关系并未改善模型拟合度（ΔOBJ，0.309）。BIS 反应的滞后时间参数可改善拟合度（ΔOBJ，89.593）。未观察到年龄或性别对其的影响。步骤 2：当前模型 PK 部分的 MDPE 和 MDAPE 分别为 11.5%（3.7-25.0）和 26.8%（20.7-32.6），PD 部分分别为 0.4%（-10.39 至 3.85）和 11.9%（20.7-32.6）。Eleveld 等人开发的 PK 模型导致最低的 PK 预测误差（MDPE = <10%和 MDAPE = <25%）。
我们推导出并验证了一种丙泊酚 PKPD 模型，以便在肥胖患者中进行效应部位 TCI。该模型仅从肥胖患者的数据中得出，不建议在瘦患者中进行 TCI，因为它有用药不足的风险。
