title: An Algorithm and R Program for Fitting and Simulation of Pharmacokinetic and Pharmacodynamic Data.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Jijie
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Mathematics, Sichuan University, China, No. 24 South Section 1, Yihuan Road, Chengdu, 610065, Sichuan, China.
authors.forename: Kewei
authors.initials: K
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Lisha
authors.initials: L
authors.lastname: Hou
authors.affiliation: 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.
authors.forename: Xudong
authors.initials: X
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: GCP Center/Institute of Clinical Pharmacology, West China Hospital of Sichuan University, China, Guoxuexiang 37#, Chengdu, 610041, Sichuan, China. lzheng2005618@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 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. cairong.zhu@hotmail.com.
authors.forename: Cairong
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D012984:Software
chemical_list: D004364:Pharmaceutical Preparations