Assessing the impacts on fetal dosimetry of the modelling of the placental transfers of xenobiotics in a pregnancy physiologically based pharmacokinetic model

Abstract

The developmental origin of health and diseases theory support the critical role of the fetal exposure to children's health. We developed a physiologically based pharmacokinetic model for human pregnancy (pPBPK) to simulate the maternal and fetal dosimetry throughout pregnancy. Four models of the placental exchanges of chemicals were assessed on ten chemicals for which maternal and fetal data were available. These models were calibrated using non-animal methods: in vitro (InV) or ex vivo (ExV) data, a semi-empirical equation (SE), or the limitation by the placental perfusion (PL).They did not impact the maternal pharmacokinetics but provided different profiles in the fetus. The PL and InV models performed well even if the PL model overpredicted the fetal exposure for some substances. The SE and ExV models showed the lowest global performance and the SE model a tendency to underprediction. The comparison of the profiles showed that the PL model predicted an increase in the fetal exposure with the pregnancy age, whereas the ExV model predicted a decrease.For the SE and InV models, a small decrease was predicted during the second trimester. All models but the ExV one, presented the highest fetal exposure at the end of the third trimester. Global sensitivity analyses highlighted the predominant influence of the transfer constants on the fetal exposure, as well as the metabolic clearance and the fraction unbound. Finally, the four transfer models could be considered depending on the framework of the use of the pPBPK model and the availability of data or resources to inform their parametrization.

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

“…Pregnancy PBPK model for renally eliminated drugs was also enhanced recently to account for ethnic differences by including specific details for Chinese pregnant populations [57]. Ongoing research regarding placental tissue structure and the consequences on fetal exposure will support enhancement of PBPK model for pregnancy applications [58,59]. The accurate predictions of both fetal Cp and amniotic fluid concentrations demonstrate the great potential of such models to impact drug development for a safety and efficacy purposes.…”

Maternal-Fetal Pharmacology of Drugs: A Review of Current Status of the Application of Physiologically Based Pharmacokinetic Models

“…A comparison of the model predictions across different trimesters of pregnancy yielded inconclusive results. These models can be optimized and potentially be used based on the purpose of the study and type of data and resources available ( 50 ). In the absence of clinical data to evaluate the fetal PBPK models, umbilical cord concentrations observed at delivery were used.…”

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

“…Yet, adequate parameterization of placental drug transfer in these models remains challenging. While some models relied on various in vitro information, such as the drug's physicochemical properties or permeability across Caco-2 cell membranes, to estimate placental drug transfer (5)(6)(7)(8), other models integrated kinetic data obtained from the ex vivo cotyledon perfusion assay (9)(10)(11)(12)(13)(14) or fitted the placental permeability to clinical data (15).…”