COMPARATIVE ANALYSIS OF SOFTWARE FOR PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING: SIMULATION, OPTIMIZATION, AND SENSITIVITY ANALYSIS

Historically, a number of different software packages running on a variety of hardware platforms have been used for model simulation. SimuSolv found wide use because of its broad capabilities, including optimization, statistical analysis, and formalized sensitivity analysis as well as the capacity to incorporate user-supplied subroutines. However, in the early 1990s, SimuSolv development ceased and a final version was released in 1993. Thus SimuSolv will not be developed for newer platforms and operating systems. In this article, we compare and contrast the use of SimuSolv and Matlab (The MathWorks, Natick, MA) for physiologically based pharmacokinetic (PBPK) model implementation with respect to parameter estimation (optimization) and sensitivity analysis using a PBPK model for trichloroethylene (TCE). In both packages, it is possible to code PBPK models, run simulations, estimate parameters, and do sensitivity analysis.The key difference is the additional programming required in Matlab. Since Matlab does not have built-in estimation and sensitivity routines, it was necessary to write them for the Matlab TCE model. Additionally, Matlab handles flow control differently from SimuSolv, so the model code is written in a different order than for SimuSolv. In spite of the additional coding requirements, Matlab is a well-supported and mathematically oriented simulation software package that is clearly suitable for application to PBPK modeling. All of the modeling tasks done in SimuSolv could also be done readily in Matlab. Most of the comparisons made to SimuSolv also carry over to ACSL-Tox, however ACSL-Tox calculates some sensitivity coefficients very differently from the way they are defined in SimuSolv. Future development of an interpreter for Matlab would make modeling, sensitivity analysis, and parameter estimation less programming-intensive.