Prediction of in vivo behavior of nanoparticles using physiologically based pharmacokinetic model: The modeling approach and issues

Abstract

The physiologically-based characteristics, the convenience of species extrapolation, and the capacity to integrate diverse in vivo mechanisms have contributed to the increasing employment of the physiologically based pharmacokinetic (PBPK) model in the pharmacokinetic and pharmacodynamic investigations of nanoparticles. However, due to the significant differences in in vivo mechanisms between nanoparticles and small molecule drugs, there are variations in the establishment of PBPK models, such as distribution mechanisms, clearance pathways, drug release, in vivo circulation pathways and indication. This review highlights the distinctions in PBPK modeling strategies between nanoparticles and small molecule drugs. It conducts a comprehensive analysis of current progress in PBPK models for nanoparticles, including model structure design, such as the setup of compartments and sub-compartments, blood circulation and lymphatic circulation, mononuclear phagocyte system, and tumor compartment; the in vivo mechanisms of nanoparticles, such as the permeability-limited mechanism, protein coronas, and drug release from nanoparticles; as well as parameter setting, including the tissue-to-plasma partition coefficient, permeability coefficient, clearance rate, and parameters related to the mononuclear phagocyte system. Ultimately, this review analyzes the validation methods and accuracy of the 61 PBPK models developed over the past two decades. In addition, several existing issues within the PBPK models for nanoparticles, along with their potential solutions, are proposed. It is anticipated that this review will be beneficial to researchers engaged in establishing PBPK models for studying the in vivo behavior of nanoparticles.