Using physiology-based pharmacokinetic modelling for mechanistic analyses of drug action in disease and special populations

Inter-individual variability in clinical endpoints and occurrence of potentially severe adverse effects may hamper drug development at all phases of (pre-)clinical research. A comprehensive understanding of drug pharmacokinetics is hence of utmost importance in drug development. Physiology-based pharmacokinetic (PBPK) models enable the mechanistic investigation of drug absorption, distribution, metabolism, and excretion at a mechanistic level of detail. This is because PBPK models describe processes governing drug pharmacokinetics based on a large amount of prior anatomical and physiological knowledge. Most notably, the computational models can be used to incorporate heterogeneous experimental data ranging from gene expression profiles at the cellular scale to physiological parameters at the whole-body level (e.g. organ volumes, blood flow rates, tissue composition) into one integrative modeling framework. We show here how targeted experimental information can support the model-based investigation of patient-specific pharmacokinetics and moreover help to explain occurrence of adverse drug reactions. Genotype-specific PBPK models of codeine, simvastatin and pravastatin will be presented which include various protein-mediated processes underlying a particular pharmacokinetic behavior, respectively. We will then show how inter-individual variability in pharmacokinetics emerges as a consequence of a patient's genetic and phenotypic predisposition. The methods presented outline how computational models together with targeted experimental data allow a mechanistic investigation of drug efficacy and even toxicity. Such integrative approaches may have significant implications for the development of individualized therapeutic strategies with a favorable risk-benefit profile in the future.