CEC03-03 Case studies of PBPK enabled safety assessments

Accurate exposure assessment is fundamental to ensuring safety in drug development. Physiologically based (pharmaco-)kinetic (PB(P)K) and organ-level mechanistic models have emerged as pivotal tools in predicting exposure over time for a target organ or tissue, in particular for small molecules. These models enable simulations across different dosing scenarios, facilitate interspecies extrapolation, help assess interindividual variability, and support in vitro to in vivo extrapolation (IVIVE). Overall, these approaches greatly promote the integration and contextualisation of in vitro data and, as a result, enhance the relevance and applicability of in vitro findings to real-world biological systems. Incorporating toxicologically relevant mechanistic in vitro data enables the quantitative evaluation of exposure-effect relationships within toxicological pathways, which are otherwise challenging to assess, thereby improving the accuracy of safety assessments.

In addition to evaluating the toxicokinetics of a compound, toxicodynamic components may be added to a PB(P)K or organ-level mechanistic model to investigate how exposure and a toxic effect are related and how an adverse effect would evolve with varying exposure over time. If data and knowledge of the mechanism of action allow for this, such approaches have the potential to greatly enhance the interpretation of in vivo toxicity testing outcomes, in particular in the context of delayed adverse effects. In complex organ systems, in which several mechanisms typically contribute to an organ-level effect, these models can help to dissect individually contributing factors. For instance, in the kidneys, damage or impairment of the vascular system may induce a secondary adverse effect on renal function through a primary damage of the renal vasculature.

This session will show some examples of how PB(P)K estimated organ-level exposure can be used to assess the risk of drug-induced adverse effects at an early stage of drug development. During this session, we will discuss common challenges and factors contributing to uncertainty underlying simulation results.

In addition, we will focus on the kidney as the target organ, and showcase examples of assessing exposure at different sections of a nephron using a human PB(P)K model coupled with a mechanistic model of the human kidney. Active and passive secretion and reabsorption processes, glomerular filtration, blood and luminal fluid flows, and metabolism will be considered. Moreover, differences of physiological parameters between young and elderly individuals will be taken into account to illustrate the power of such models in investigating vulnerable populations.