Application of Physiologically-Based Pharmacokinetic (PBPK) Model in Drug Development and in Dietary Phytochemicals

Abstract Purpose of review Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to understand drug movements throughout the human body. Unlike classical PK methods that often lack sufficient physiological detail, PBPK integrates drug-specific properties with organism-specific physiological parameters to predict drug behavior in major body compartments, particularly site of action and providing high physiological realism. The aim of the review is to summarize application of PBPK modeling in drug development and in dietary phytochemicals. Recent findings PBPK modeling is a versatile tool in drug development and phytochemical research. It predicts human PK from preclinical data, aiding lead optimization and candidate evaluation. The model mechanistically predicts drug-drug interactions (DDIs), supporting dose adjustments and reducing clinical trials. PBPK also enables formulation simulation for oral and modified-release drugs, optimizing bioavailability and predicting performance from in vitro data, thus reducing costly in vivo studies. Importantly, it extends drug knowledge to pediatric and special populations via virtual group simulations, enabling efficient, cost-effective dosage determination and less clinical trials. For dietary phytochemicals, PBPK modeling is well-suited for their complex mixture and variability. PBPK studies of phytochemicals demonstrate their utility for single components, mixtures, cross-species extrapolation, and complex metabolic processes, although challenges exist. Summary PBPK modeling is a dynamic and quantitative tool offering comprehensive pharmacokinetic integration across various populations and regimens. Its importance is growing due to its application at diverse stages of drug development and its ability to adapt to complex substances, including natural products. Ultimately, PBPK modeling is significant for enhancing scientific rigor, expediting drug development and ensuring patient safety. Graphical Abstract