Applications of Physiologically-Based Pharmacokinetic (PBPK) Modeling in Discovery and Development of Cancer Chemotherapeutic Drugs

Abstract

Cancer drug discovery and development has been a particular research interest worldwide and has been rapidly increased over the last two decades.  Although several compounds were evaluated for potential anticancer activities, the number of anticancer drugs approved by U.S. FDA during 2006-2015 tended to decrease and only 5.1% of drug in Phase 1 clinical trials were approved.  Most of the failures occurred during clinical trials were due to inadequate supportive data of pharmacokinetic-pharmacodynamic relationship. Physiologically-based pharmaco-kinetic model (PBPK) is a computational model simulating human physiology that can predict the plasma/blood and the tissue concentrations of the drug of interest. Several PBPK models have been developed and applied to the various phases in order to reduce time and costs of the drug development. This review consists of three main parts. The first part is the classification and the description of model structure. The second part is the description of theories and mathematical model equations, i.e., perfusion-limited model, first-order kinetics, and Michaelis-Menten kinetics. Model parameters include the drug-specific parameters and the human physiological parameters. The examples of drug-specific parameters are the intrinsic clearance, tissue-to-plasma partition ratio, and the fraction of unbound drug. The examples of human physiological parameters are organ volume, and organ weight. The third part is the applications of PBPK model in non-clinical and clinical development phases. The major problem of PBPK model is the physiological differences between animals and humans which affect accuracy and precision of the prediction. This obstacle challenges the future development of the PBPK models.