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

Abstract

AIMSPregnant 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. METHODSTransplacental 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. RESULTSParameters 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.

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

“…Various models have previously been presented that allow the prediction of concentrations in the fetal blood or tissues . The 2 most promising approaches for predicting the transfer of a compound across the placenta were those presented by De Sousa Mendes et al and by Zhang et al . The approach suggested by Mendes et al relies on experimental data obtained from the ex vivo cotyledon perfusion experiment.…”

“…Thereafter, these parameters were integrated in a whole‐body PBPK model. It was shown that through this approach, the pharmacokinetics of emtricitabine, tenofovir, and nevirapine observed at delivery could adequately be predicted by the PBPK model . One shortcoming of this approach is that it cannot be readily extrapolated to other compounds for which no data from the ex vivo cotyledon perfusion experiment are available.…”

“…Various models have previously been presented that allow the prediction of concentrations in the fetal blood or tissues. [92][93][94][95][96][97] The 2 most promising approaches for predicting the transfer of a compound across the placenta were those presented by De Sousa Mendes et al 94,95 and by Zhang et al 96 The approach suggested by Mendes et al relies on experimental data obtained from the ex vivo cotyledon perfusion experiment. Briefly, a 4compartment model is used to describe these data, and the key parameters governing the placental transfer (the placental transfer constant and the partition coefficient) were initially fitted to the experimental data.…”

Physiologically Based Pharmacokinetic Modeling in Pregnancy: A Systematic Review of Published Models

“…Of note, originating from the Simcyp pregnancy model, more mechanistic PBPK models were recently developed in R, 46,47 MatLab, 40,48 and Berkeley Madonna. 49 Instead of a lumped fetoplacental unit, the models developed in R and MatLab incorporate four separate compartments representing the amniotic fluid, fetal body, fetal blood, and the placenta.…”

“…Another approach has been proposed by De Sousa Mendes et al, who estimated placental transfer rates for tenofovir, emtricitabine, and nevirapine from ex vivo placenta perfusion experiments. 46,47 The estimated transfer rates were subsequently implemented in a PBPK model framework and fetal exposure was adequately predicted. Schalkwijk et al employed a very similar approach for predicting fetal darunavir exposure.…”