1. JGuiB - AN ASSISTANT TOOL FOR PHARMACOKINETIC/PHARMACODYNAMIC MODELING WORKING WITH BOOMER Ying-hao Lu 1 *, David W.A. Bourne 2, Yung-jin Lee 1 1 College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan 2 College of Pharmacy, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73119, U.S.A. Introduction BOOMER (www.BOOMER.org) created by David W.A. Bourne is an excellent non-linear regression tool for data analysis and modeling of pharmacokinetic (PK) and pharmacodynamic (PD) data. 1 It is very suitable for purposes of computer- aided PK/PD modeling teaching and data analysis with many built-in numerical integration and nonlinear optimization algorithms. Unfortunately, BOOMER only runs in a menu driven mode under different platforms. Therefore it may take time for a beginner to learn how to use it in PK/PD modeling. The purpose of this study was to build a GUI (Graphical User Interface) for BOOMER to assist users who need a GUI to manipulate the operation of BOOMER.www.BOOMER.org Keywords: BOOMER, JGuiB, PK/PD Modeling, Non-linear Regression, Java, Java SE Methods and Materials When starting to build the GUI, the first problem we had to solve was to modify BOOMER to accept command-line instructions. In order to make the GUI work with BOOMER under background, BOOMER was modified to be able to run under command-line mode. This allowed the operation of BOOMER controlled by the GUI generated batch files. Since BOOMER has the cross-platform property to run on Mac OS X, Windows and Linux, our GUI should exploit this property. Thus we selected Java (Java SE) as programming language to build our GUI, and used JBuilder X Foundation, a powerful Java IDE (Integrated Development Environment), as developer and compiler. We call this GUI as JGuiB, which stands for Java GUI for BOOMER. Results and Discussion We have successfully turned the menu-driven mode of BOOMER into a GUI-based application with JGuiB. JGuiB with BOOMER can run in platforms of Mac OS X, Windows and Linux. Three main BOOMER functions in PK/PD modeling are supported: normal fitting, simulation and Bayesian estimation. Users just follow the sequences of PK/PD modeling (model building/selection), data manipulation (spreadsheet-like data editing; copy and paste) and weighting scheme selections, and finally numerical integration/nonlinear optimization selections through GUI and run this project with BOOMER. Twenty four frequently used PK/PD models with graphics were built and included with JGuiB. JGuiB also allows users to build their defined PK/PD models with a panel of“Parameter Table”, such as physiologically based pharmacokinetic (PBPK) model. To avoid possible input errors made by users, JGuiB is designed to lessen user’s inputs, such as without assigning “lower limit” and “upper limit” for each adjustable parameter. Two of more fascinating functions of JGuiB are that: (1) it provides the clinical-oriented Bayesian estimation functions with multiple-dosing modeling functions for uniform or non-uniform doses, 2 and (2) it enables BOOMER to simultaneously work with different PK/PD models (max. 4 models in one project file) using the same set of data for the purpose of model discrimination (Figure 1). We contrast BOOMER with JGuiB plus BOOMER in Table 1, 3 and compare JGuiB plus BOOMER with WinNonlin in Table 2. 4 Finally there are the screenshots of JGuiB to show how to use it with friendly-to-use functions in Figure 2. Conclusion and Future Works JGuiB has been successfully built and it is just a GUI, an assistant tool for BOOMER in PK/PD modeling. It generates a batch file (Input file) which is subsequently analyzed using BOOMER which provides the computational engine. Therefore, JGuiB is dependent on BOOMER. The built-in PK model library in JGuiB enables users to apply these models quickly to analyze data with BOOMER. Boomer also can easily apply to multiple dosing modeling and Bayesian estimation into the field of clinical pharmacokinetic services with excellent model building templates and easy-to-use data management of JGuiB. Therefore, JGuiB effectively extends the abilities of Boomer. In conclusion, JGuiB is the first GUI program for individual PK/PD software in the world. In the future, we plan to enhance the modeling automation of JGuiB to include PBPK modeling and Monte Carlo simulation. In addition, we will continue to develop JGuiB including more functions provided by BOOMER, and enhance its ease of use. JGuiB can be freely downloaded from http://jguib.pkpd.org.tw/.http://jguib.pkpd.org.tw/ References 1.Bourne DWA, BOOMER, 1989, a simulation and modeling program for pharmacokinetic and pharmacodynamic data analysis. Computer Methods and Programs in Biomedicine, 29: 191-95 2.Yamaoka K, Nakagawa T, Tanaka H, Yasuhara M, Okumura K, Hori R, 1985, A nonlinear multiple regression program, MULTI2 (BAYES), based on Bayesian algorithm for microcomputers. Journal of Pharmacobio-Dynamic, 8: 246-56. Table 1 - Comparison of BOOMER and JGuiB (+ BOOMER) 3 ProgramFormatCoding Language Platform # MacOSMacOS XWindowsLinux BOOMER Menu-DrivenFORTRANYes JGuiB (+ BOOMER) Graphic InterfaceJAVANoYes ProgramModel No.Subject No.Data ManagementError CheckLower Limit/Upper LimitHelp Function BOOMER 1*1* 1*1* From Keyboard a FewUsers supply Online Manual (www.BOOMER.org)www.BOOMER.org From Data file JGuiB (+ BOOMER) max. 4 ** no limitation ** Excel-Formatted Data Exchange CompleteJGuiB Generates (10 -8 /10 +8 )Some Helpful functions *** copy & paste Program PK/PD Modeling Functions Normal FittingNormal SimulationBayesian EstimationMonte-Carlo SimulationMultiple Dosage Regimens BOOMER Yes JGuiB (+ BOOMER) Yes NoYes * from each batch file ** from each project file (JGuiB can generate many batch files) *** a. support some project files for examples. b. visualized model graphs in built-in library. c. helpful video demo when linking to JGuiB website (http://jguib.pkpd.org.tw/). d. parameter type lists, parameter properties lists, error type lists.http://jguib.pkpd.org.tw/ # BOOMER Version (Mac OS X, Windows, Linux: 3.3.2), JGuiB Version (2.1) Table 2 - Comparison of JGuiB (+ BOOMER) and WinNonlin 4 ProgramVersion ReviewedGraphic Interface Platform Initial Parameter Value Lower Limit/ Upper Limit MacOS XWindowsLinux JGuiB (+ BOOMER) 2.1Yes Users SupplyJGuiB Generates WinNonlin 4.1YesNoYesNo Users Supply WinNonlin Generates Program Excel-compatible spreadsheet PlottingAUC/AUMC CalculationPrintCharge JGuiB (+ BOOMER) Yes Linear Trapezoidal Rule Yes$59.95 Method 9 of R.D. Purves WinNonlin Yes Linear Trapezoidal RuleYes$1000/year ProgramNonlinear OptimizationWeighting Scheme* JGuiB (+ BOOMER) Gauss Newton AlgorithmSimplex AlgorithmEqual Weighting1/Y1/Y^2 Marquardt AlgorithmDamping Gauss Newton Algorithm 1/a*Y^b1/(a+b*Y^c)1/[(a+b*Y^c)*d^(tn-ti)] Simplex to Damping Gauss Newton Algorithm WinNonlin Gauss Newton AlgorithmSimplex Algorithm Equal Weighting 1/Y1/Y^21/Y^(1/2) Program PK/PD Modeling Functions PK ModelPD ModelPK/PD ModelPBPK ** ModelNCA *** Model Macro-constant Exponential Model JGuiB (+ BOOMER) Yes WinNonlin Yes NoYes Program PK/PD Modeling Functions Built-in Library User’s Defined Library Bayesian Estimation DefinitionNo. JGuiB (+ BOOMER) Differential Equation24Differential EquationYes WinNonlin Integrated Equation37Differential EquationNo * BOOMER allows explicit entry of weight as third data column, but JGuiB just supports the weighting scheme selections for the data sets. a, b, c, d - constants ** Physiologically-Based Pharmacokinetic *** Non-Compartmental Analysis Figure 1 - JGuiB (+ BOOMER) can generates 20 output files in the same subject data working with 4 PK/PD models. Figure 2 - the screenshots of JGuiB to show how to use it with friendly-to-use functions. 3.Boomer Website, 2006, http://www.BOOMER.org 4.WinNonlin Website, 2006, http://www.pharsight.com/products/winnonlin/