Recent applications of physiologically based pharmacokinetic modeling to assess the toxicity of mixtures: A review

Abstract

In this article, we review recent research in the application of PBPK modeling to chemical mixtures, focusing on the previous three years. The scope of the review included both isozyme-specific modeling of drug–drug interactions and modeling of complex environmental mixtures. Recent pharmaceutical-related modeling efforts continue to advance the state of the art for predicting both pharmacokinetic and pharmacodynamic interactions. In contrast, recent studies on modeling of environmental mixtures have often assumed that the human exposures are too low to drive metabolic interactions, and evaluations of complex mixtures have shifted focus to assessing the potential for PD interactions. Future progress in this area is hindered by the fact that the available PBPK platforms for modeling drug–drug interactions are not designed to support interaction modeling for more than two compounds. While this limitation may not be of concern for pharmaceuticals, it severely limits potential applications to environmental mixtures. Widespread application of PBPK interaction modeling to complex mixtures will require the development of user-friendly, web-based applications that allow individuals from a wide variety of disciplines to exercise the models. The Open Systems Pharmacology suite (PK-Sim and Mobi) may provide a useful platform for this purpose.