Combining Systems Biology with Physiologically Based Pharmacokinetics to Support the Understanding of Drug Effects

Abstract

To increase the efficiency of drug discovery and development, modelling and simulation in pharmacokinetics and disease is gaining increasing attraction. Due to recent advances in physiologically based pharmacokinetics regarding the prediction of key parameters, it is now possible to predict concentration-time profiles in different spaces of various organs for large classes of compounds—even prior to the performance of any in vivo studies. The field has now reached a status that allows for ample exploitation on a much broader scale. Combined with systems biology models of cellular response at the target site this will result in more realistic mechanism based pharmacokinetic/dynamic models with a wide spectrum of important applications in current drug design, including e.g., identification and ranking of biomarkers candidates, time resolved analysis of drug-target interactions, support in prioritizing compounds, and the study of physiological variability and important sub-populations. First steps of this combined approach are illustrated for diabetes mellitus type 2 treatment with tolbutamide, and the implications on the design requirements for the systems biology models are discussed.