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Susana Proenca
Wageningen University

Following her master’s degree, Susana Proença undertook a traineeship at ECVAM within the  JRC, where she began working with the Virtual Cell-Based Assay and became acquainted with in vitro kinetics models. After, she started her PhD at the Institute for Risk Assessment Sciences,  Utrecht University, with associate professor Nynke Kramer. The PhD focuses on further understanding and measuring in vivo distribution kinetics of certain chemicals in the context of the Marie-Curie Training network in3. She moved to Wageningen University with her supervisor  Nynke Kramer in June 2022 to work on in vitro kinetics in the ONTOX project. She recently joined esqLABS, where she will also be working on the EU-funded ONTOX and other projects involving the development strategies of QIVIVE.

OpenTox Virtual Conference 2023 

In vitro kinetics as a cornerstone for QIVIVE and IVIVE

The free drug hypothesis postulates that only free drug molecules can interact with biological molecules, having substantial implications in the fields of toxicokinetics and toxicodynamics. It  implies that the ideal dose metric for extrapolations between biological models, specifically in In  Vitro to In Vivo Extrapolation (IVIVE) and Quantitative In Vitro to In Vivo Extrapolation (QIVIVE),  is the concentration of free drug at the target site, whether it be specific tissues or cells. 

Physiologically Based Kinetic (PBK) models are crucial, allowing the simulation of in vivo kinetics processes to ascertain the free concentration at the target site in time. Although the in vitro environment is inherently simpler, various factors within it, including binding to serum proteins or lipids, adhesion to plastic, and evaporation, significantly influence the availability of test chemicals. In recent years, recognition of these in vitro kinetic processes has increased in the scientific community, as multiple in silico models have emerged to predict these in vitro kinetic processes. These models integrate with a variety of compartments and processes, and while  some of these models focus on specific chemicals using experimental data fitting, others opt for a broader approach, leveraging Quantitative Structure-Activity Relationships  

(QSARs) to predict partition coefficients or rates. Examples will be provided to demonstrate the application of these in vitro kinetic models, not only in identifying optimal dose metrics in vitro models subject to repeated exposure but also in extrapolating in vitro-derived kinetic parameters to in vivo scenarios. 

However, the applicability domains of these models of in vitro kinetics, both biologically and chemically, are limited. Notable gaps exist, particularly for advanced in vitro models like those deployed in the EU-funded ONTOX project and chemicals that remain unexplored within the  QSAR training sets. Expanding the applicability domains of these models is crucial for the accuracy of IVIVE and QIVIVE, particularly in initiatives such as ONTOX, fulfilling the promise of  Next Generation Risk Assessment.