CEC03-04 PBPK and QST for safety assessments

Abstract

The integration of physiologically based pharmacokinetic (PBPK) modeling with quantitative systems toxicology (QST) represents a mechanistic framework to support modern safety assessments. While PBPK models can support the simulation of concentrations across tissues and species, QST adds a dynamic layer that captures biological processes underlying toxicity at the organ and systems level.

Together, these approaches enable a more comprehensive understanding of dose–response relationships by linking predicted exposure to biologically relevant modes of action. This is particularly valuable when translating in vitro or nonclinical data into quantitative human-relevant outcomes. By coupling kinetic and dynamic models, it becomes possible to identify points of departure based on mechanistic approaches and supported by predicted concentrations, rather than relying on empirical thresholds or safety factors.

In this session, we will explore how PBPK-QST integration enhances the relevance and reproducibility of safety evaluations, supports the reduction of animal use, and aligns with current trends in regulatory science. The presentation will also reflect on how modular, open-source modeling ecosystems contribute to greater transparency and flexibility in model development, qualification, and application across sectors.

Overall, PBPK-QST frameworks represent a strategic step forward in next-generation risk assessment by providing a quantitative and mechanistic basis for predicting toxicity, refining uncertainty, and supporting evidence-based decisions in both pharmaceutical and non-pharmaceutical contexts.