Li Jijie, Yan Kewei, Hou Lisha, Du Xudong, Zhu Ping, Zheng Li, Zhu Cairong
Department of Epidemiology and Biostatistics, West China School of Public Health, Sichuan University, China, No. 17 Section 3, Renmin South Road, Chengdu, 610041, Sichuan, China.
College of Mathematics, Sichuan University, China, No. 24 South Section 1, Yihuan Road, Chengdu, 610065, Sichuan, China.
Eur J Drug Metab Pharmacokinet. 2017 Jun;42(3):499-518. doi: 10.1007/s13318-016-0358-x.
Pharmacokinetic/pharmacodynamic link models are widely used in dose-finding studies. By applying such models, the results of initial pharmacokinetic/pharmacodynamic studies can be used to predict the potential therapeutic dose range. This knowledge can improve the design of later comparative large-scale clinical trials by reducing the number of participants and saving time and resources. However, the modeling process can be challenging, time consuming, and costly, even when using cutting-edge, powerful pharmacological software. Here, we provide a freely available R program for expediently analyzing pharmacokinetic/pharmacodynamic data, including data importation, parameter estimation, simulation, and model diagnostics.
First, we explain the theory related to the establishment of the pharmacokinetic/pharmacodynamic link model. Subsequently, we present the algorithms used for parameter estimation and potential therapeutic dose computation. The implementation of the R program is illustrated by a clinical example. The software package is then validated by comparing the model parameters and the goodness-of-fit statistics generated by our R package with those generated by the widely used pharmacological software WinNonlin.
The pharmacokinetic and pharmacodynamic parameters as well as the potential recommended therapeutic dose can be acquired with the R package. The validation process shows that the parameters estimated using our package are satisfactory.
The R program developed and presented here provides pharmacokinetic researchers with a simple and easy-to-access tool for pharmacokinetic/pharmacodynamic analysis on personal computers.
药代动力学/药效学连接模型在剂量探索研究中广泛应用。通过应用此类模型，初始药代动力学/药效学研究结果可用于预测潜在治疗剂量范围。这一知识可通过减少参与者数量、节省时间和资源来改进后续比较大规模临床试验的设计。然而，建模过程可能具有挑战性、耗时且成本高昂，即便使用前沿、强大的药理学软件亦是如此。在此，我们提供一个免费的R程序，用于便捷地分析药代动力学/药效学数据，包括数据导入、参数估计、模拟和模型诊断。
首先，我们解释与药代动力学/药效学连接模型建立相关的理论。随后，我们介绍用于参数估计和潜在治疗剂量计算的算法。通过一个临床实例说明R程序的实现。然后通过将我们的R软件包生成的模型参数和拟合优度统计量与广泛使用的药理学软件WinNonlin生成的进行比较，对该软件包进行验证。
使用该R软件包可获取药代动力学和药效学参数以及潜在推荐治疗剂量。验证过程表明，使用我们的软件包估计的参数令人满意。
此处开发并展示的R程序为药代动力学研究人员提供了一个简单且易于在个人计算机上进行药代动力学/药效学分析的工具。
