Paramétrisation des modèles physiologiques toxico/pharmacocinétiques

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 the model complexity, the large number of parameters, and the amount of toxicokinetic data available (typically, few and sparse). To overcome these difficulties, we propose to develop two experimental protocols to parameterize PBPK models: the gathering of data on the spatio-temporal distribution of a substance in the body by imaging techniques, and the use of non-toxic tracer (or probe) for toxicokinetic studies. These two protocols should bring 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®. Thanks to the modeling of the experimental data obtained with magnetic resonance imaging, we have characterized the whole-body vascularization, and the one of a grafted tumor. Moreover, we evaluated statistically 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 4 in our example) while maintaining precision 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 to apply 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 yields to a better determination of the action of the substance of interest. A logical following of our work is to couple the two protocols, that is to say to develop exposure scenarios to a toxicant and to a substance that can be followed by an imaging technique.
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Céline Brochot. Paramétrisation des modèles physiologiques toxico/pharmacocinétiques. Sciences du Vivant [q-bio]. Université Pierre et Marie Curie - Paris VI, 2004. Français. ⟨tel-00107374⟩

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