Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling of Nanomaterials.

Nanoparticles (NPs) have been widely used to improve the pharmacokinetic properties and tissue distribution of small molecules such as targeting to a specific tissue of interest, enhancing their systemic circulation, and enlarging their therapeutic properties. NPs have unique and complicated in vivo disposition properties compared to small molecule drugs due to their complex multifunctionality. Physiologically based pharmacokinetic (PBPK) modeling has been a powerful tool in the simulation of the absorption, distribution, metabolism, and elimination (ADME) characteristics of the materials, and it can be used in the characterization and prediction of the systemic disposition, toxicity, efficacy, and target exposure of various types of nanoparticles. In this review, recent advances in PBPK model applications related to the nanoparticles with unique properties, and dispositional features in the biological systems, ADME characteristics, the description of transport processes of nanoparticles in the PBPK model, and the challenges in PBPK model development of nanoparticles are delineated and juxtaposed with those encountered in small molecule models. Nanoparticle related, non-nanoparticle-related, and interspecies-scaling methods applied in PBPK modeling are reviewed. In vitro to in vivo extrapolation (IVIVE) methods being a promising computational tool to provide in vivo predictions from the results of in vitro and in silico studies are discussed. Finally, as a recent advancement ML/AI-based approaches and challenges in PBPK modeling in the estimation of ADME parameters and pharmacokinetic (PK) analysis results are introduced.