Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations

Abstract

In vitro toxicokinetic data are critical in meeting an increased regulatory need to improve chemical safety evaluations towards a better understanding of internal human chemical exposure and toxicity. In vitro intrinsic hepatic clearance (CLint), the fraction unbound in plasma (Fup), and the intestinal apparent permeability (Papp) are important parameters as input in a physiologically based kinetic (PBK) model to make first estimates of internal exposure after oral dosing. In the present study we explored the experimental variation in the values for these parameters as reported in the literature. Furthermore, the impact that this experimental variation has on PBK model predictions of maximum plasma concentration (Cmax) and the area under the concentration time curve (AUC0-24h) was determined. As a result of the experimental variation in CLint, Papp, and Fup, the predicted variation in Cmax for individual compounds ranged between 1.4-to 28-fold and the predicted variation in AUC0-24h ranged between 1.4-and 23-fold. These results indicate that there are still some important steps to take to achieve robust data that can be used in regulatory applications. To gain regulatory acceptance of in vitro kinetic data and PBK models based on in vitro input data, the boundaries in experimental conditions as well as the applicability domain and the use of different in vitro kinetic models need to be described in guidance documents.

From Pipeline to Plant Protection Products: Using New Approach Methodologies (NAMs) in Agrochemical Safety Assessment

“…26 ■ METABOLISM AND TOXICOKINETIC MODELING Generic PBPK models can be used to predict basic kinetics properties of the A.S. 27 These assays can be off-the shelf commercial models or the basic HTTK model, like those outlined in the USEPA presentation "Rapid PBPK modeling with the HTTK model". 28 These can also be occasionally parametrized with high throughput screenings for certain kinetic parameters, such as Caco-2 cell screening for oral absorption, 29 liver microsomal clearance for metabolism kinetics, 30 and plasma protein binding 31 for distribution kinetics. Further evaluation of metabolic stability and pathways is key to predicting the fate of a pesticide in the environment, which is critical to the assessment of the potential exposure and risks to humans and ecological systems.…”

Metabolites in the regulatory risk assessment of pesticides in the EU

“…It must be noted that the testing approach described in the scientific opinion (EFSA PPR Panel et al, 2021b) was not developed to obtain chemical-specific input parameters for PBK models. It is therefore recommended to develop a harmonised guidance to highlight the requirements for generating reliable chemical-specific input parameters for PBK models and illustrate their use through relevant case studies so that these can be used for regulatory applications as demonstrated recently in the OECD guidance and related case studies (OECD, 2021a, b;Paini et al, 2019;Punt et al, 2023).…”