Optimization of individual and population designs using Splus

Abstract

We address the problem of design optimization for individual and population pharmacokinetic studies. We develop Splus generic functions for pharmacokinetic design optimization: IFIM, a function for individual design optimization similar to the ADAPT II software, and PFIM_OPT, a function for population design optimization which is an extension of the Splus function PFIM for population design evaluation. Both evaluate and optimise designs using the Simplex algorithm. IFIM optimizes the sampling times in continuous intervals of times; PFIM_OPT optimizes either, for a given group structure of the population design, only the sampling times taken in some given continuous intervals or, both the sampling times and the group structure, performing then statistical optimization. A combined variance error model can be supplied with the possibility to include parameters of the error model as parameters to be estimated. The performance of the optimization with the Simplex algorithm is demonstrated with two pharmacokinetic examples: by comparison of the optimized designs to those of the ADAPT II software for IFIM, and to those obtained using a grid search or the Fedorov-Wynn algorithm for PFIM_OPT. The influence of the variance error model on design optimization was investigated. For a given total number of samples, different group structures of a population design are compared, showing their influence on the population design efficiency. The functions IFIM and PFIM_OPT offer new efficient solutions for the increasingly important task of optimization of individual or population pharmacokinetic designs.