Prédiction du passage transplacentaire in-vivo des médicaments à partir de modèles ex-vivo

Abstract : Pregnant women are exposed to numerous drugs and for obvious ethical reasons studies in this sensitive population arelimited. Information about the maternal pharmacokinetic (PK) changes and transplacental transfer of drugs prior to theiradministration to pregnant women would be highly useful. Indeed is it known that physiological changes during pregnancycan affect drug disposition. Time-varying pregnancy-related physiological parameters changes were implemented in fullPBPK models. They successfully predicted the disposition of 3 renally excreted drugs tenofovir (TFV), emtricitabine (FTC)and lamivudine (3TC) and one metabolized drug, nevirapine (NVP) for non-pregnant and pregnant populations. We foundthat both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related tochanges in renal plasma flow. Transplacental parameters estimated from ex vivo human placenta perfusion experiments implemented in PBPK models allowed good prediction of foetal TFV, FTC and NVP PK. Predictions were compared to observed cord blood concentrations to validate these models. Moreover, we have explored nevirapine foetal metabolism and concluded that even if the foetal metabolism is the same than the newborn one or a little more important, it is notlikely to impact foetal PK.
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Maïlys De Sousa Mendes. Prédiction du passage transplacentaire in-vivo des médicaments à partir de modèles ex-vivo. Pharmacologie. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB144⟩. ⟨tel-01977950⟩

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