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Modélisation pharmacocinétique et pharmacodynamique de la toxicité développementale de l'embryon de poisson zèbre.

Abstract : In risk assessment, understanding and predicting the effects of chemical compounds on the development of living beings are needed to understand and manage environmental and therapeutic toxicity. Due to its many experimental and regulatory advantages, and genetic homologies with humans, the zebrafish embryo is widely used for toxicity testing. As part of the European project Eu-ToxRisk,the objective of this work was to improve the extrapolation of the zebrafish embryo data to humans by developingtwo mathematical models able to explain and predict the occurrence of malformations during the zebrafish embryo first five days of development, following exposure valproic acid (VPA), a notorious teratogen, and nine of its analogues.First, a generic physiology-based pharmacokinetic model (PBPK) able to predict the concentrations of neutral or ionizable compounds in ten embryonic organs of interest. Organ growth is considered and the culture medium to organ partition coefficients are predicted by a QSAR sub-model. Metabolic clearance and a partition coefficient correction factor weresimultaneously estimated by Bayesian calibration of the model with embryo and culture medium concentration data of VPA and its analogues over five days of repeated dosing. Second, a multi-state Markovian pharmacodynamic (PD) model to predict the occurrence of malformations as a function of time and VPA exposure concentration. Finally, to describe the behavior of VPA in the embryo and the impact of time and exposure on malformations, the two models were coupled to generate a PK-PD model. The average internal concentration of VPA, predicted by the PBPK model, controls random transitions between states. By Bayesian calibration with malformation data, the transition rates between states were estimated, allowing estimation oftransition probabilities and associated effective concentrations.
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Submitted on : Tuesday, March 30, 2021 - 9:30:34 AM
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Ségolène Siméon. Modélisation pharmacocinétique et pharmacodynamique de la toxicité développementale de l'embryon de poisson zèbre.. Biologie de la reproduction. Institut agronomique, vétérinaire et forestier de France, 2020. Français. ⟨NNT : 2020IAVF0020⟩. ⟨tel-03185019⟩

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