Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models.

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.