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Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models
Author(s) -
De Sousa Mendes Maïlys,
Hirt Deborah,
Vinot Cécile,
Valade Elodie,
Lui Gabrielle,
Pressiat Claire,
Bouazza Naïm,
Foissac Frantz,
Blanche Stephane,
Lê Minh Patrick,
Peytavin Gilles,
Treluyer JeanMarc,
Urien Saik,
Benaboud Sihem
Publication year - 2016
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12815
Subject(s) - transplacental , ex vivo , pharmacokinetics , fetus , physiologically based pharmacokinetic modelling , medicine , in vivo , cord blood , pharmacology , placenta , perfusion , physiology , pregnancy , biology , microbiology and biotechnology , genetics
AIMS Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. Methods Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy–physiologically based pharmacokinetic (p‐PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. Results Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo . Conclusion The integration of ex vivo human placental perfusion parameters in a p‐PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.