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La modélisation physiologique en toxicologie

Abstract : Physiologically-based pharmacokinetic (PBPK) models are used to describe the biodistribution (administration, distribution, metabolism and excretion) of substances in the body. However, fitting a PBPK model to experimental data can be difficult because of model complexity, the large number of parameters and the amount of toxicokinetic data available (typically, few and sparse). To overcome these difficulties, we propose developing two experimental protocols to parameterize PBPK models: the gathering of data on the spatiotemporal distribution of a substance in the body by imaging techniques, and the use of a non-toxic tracer (or probe) for toxicokinetic studies. These two protocols should provide complementary information for the model parameters. For the first protocol, we applied image analysis to the development of a PBPK model for a contrast agent, Vistarem®. Through modelling of the experimental data obtained with magnetic resonance imaging, we characterized the wholebody vascularization, and the vascularization of a grafted tumour. Moreover, we statistically evaluated the effects of an antiangiogenic treatment. We also introduced the use of probes in toxicokinetic studies. We developed exposure scenarios to a chemical and to a probe for humans. With simulated data, we showed that it is possible to reduce the toxic exposure dose (by a factor of 4 in our example) while maintaining accuracy in parameter estimates, if the toxic exposure is completed with an exposure to a probe. The main disadvantage of this protocol is the complexity of the data analysis (two PBPK model calibrations should be performed). To reduce this complexity, we proposed applying lumping methods. Such methods aim at reducing differential equation systems. With simple examples, we showed their usefulness for toxico/pharmacokinetic models. Each protocol developed here includes a supplementary substance. Our work shows that the use of this substance reinforces knowledge on the anatomy and physiology of the subject studied. This results in a better determination of the action of the substance of interest.
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https://hal-ineris.archives-ouvertes.fr/ineris-01869082
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  • HAL Id : ineris-01869082, version 1

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Céline Brochot, Sandrine Micallef, Frédéric Y. Bois. La modélisation physiologique en toxicologie. Rapport Scientifique INERIS, 2007, 2006-2007, pp.30-33. ⟨ineris-01869082⟩

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