Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

The assessment of human fetal exposure to chemicals is a key to fully understand developmental toxicity. Maternal concentrations during pregnancy and cord blood concentrations at delivery are often used as a proxy of fetal exposure over pregnancy or at term, respectively. Pregnancy physiologically-based pharmacokinetic (pPBPK) models can serve as an alternative by simulating fetal exposure throughout gestation. The latter depends on the maternal pharmacokinetic absorption, distribution, metabolism and elimination (ADME) processes, but also largely on placental transfers. Various placental transfer structures are used in pPBPK models and they are informed by numerous data sources. In this paper, we reviewed the physiological and anatomical changes of the placenta during human pregnancy, and the various placental transfer sub-models which have been used in animal and human pPBPK modeling. Computational and experimental methods used to characterize placental transfers are presented and discussed for their potential contribution to the development or evaluation of pPBPK models. This review provides information to support a reasoned-decision upon the integration of placental transfer in pPBPK modeling to better investigate fetal toxicokinetics in silico. © 2019 Elsevier B.V.