Pharmacometrics Group, Dept of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
J Pharmacokinet Pharmacodyn. 2012 Apr;39(2):177-93. doi: 10.1007/s10928-012-9240-x. Epub 2012 Jan 21.
The aim of this study is to present and evaluate an alternative sequential method to perform population pharmacokinetic-pharmacodynamic (PKPD) analysis. Simultaneous PKPD analysis (SIM) is generally considered the reference method but may be computationally burdensome and time consuming. Evaluation of alternative approaches aims at speeding up the computation time and stabilizing the estimation of the models, while estimating the model parameters with good enough precision. The IPPSE method presented here uses the individual PK parameter estimates and their uncertainty (SE) to propagate the PK information to the PD estimation step, while the IPP method uses the individual PK parameters only and the PPP&D method utilizes the PK data. Data sets (n = 200) with various study designs were simulated according to a one-compartment PK model and a direct Emax PD model. The study design of each dataset was randomly selected. The same PK and PD models were fitted to the simulated observations using the SIM, IPP, PPP&D and IPPSE methods. The performances of the methods were compared with respect to estimation precision and bias, and computation time. Estimated precision and bias for the IPPSE method were similar to that of SIM and PPP&D, while IPP had higher bias and imprecision. Compared with the SIM method, IPPSE saved more computation time (61%) than PPP&D (39%), while IPP remained the fastest method (86% run time saved). The IPPSE method is a promising alternative for PKPD analysis, combining the advantages of the SIM (higher precision and lower bias of parameter estimates) and the IPP (shorter run time) methods.
本研究旨在提出并评估一种替代的序贯方法来进行群体药代动力学-药效学（PKPD）分析。同时进行 PKPD 分析（SIM）通常被认为是参考方法，但可能计算量大且耗时。评估替代方法的目的是加快计算时间并稳定模型的估计，同时以足够好的精度估计模型参数。本文提出的 IPPSE 方法使用个体 PK 参数估计值及其不确定性（SE）将 PK 信息传播到 PD 估计步骤，而 IPP 方法仅使用个体 PK 参数，PPP&D 方法则利用 PK 数据。根据单室 PK 模型和直接 Emax PD 模型，根据各种研究设计模拟了数据集（n=200）。每个数据集的研究设计是随机选择的。使用 SIM、IPP、PPP&D 和 IPPSE 方法拟合相同的 PK 和 PD 模型到模拟观测值。比较了方法在估计精度和偏差以及计算时间方面的性能。IPPSE 方法的估计精度和偏差与 SIM 和 PPP&D 相似，而 IPP 的偏差和不精确性更高。与 SIM 方法相比，IPPSE 比 PPP&D 节省了更多的计算时间（61%），而 IPP 仍然是最快的方法（节省 86%的运行时间）。IPPSE 方法是 PKPD 分析的一种有前途的替代方法，结合了 SIM（更高的参数估计精度和更低的偏差）和 IPP（更短的运行时间）方法的优点。
