Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses

Abstract

Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age-dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: 1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug-dosing regimens administered to the mother; 2) predict the impact of gestational age on fetal drug exposure; and 3) demonstrate that a single umbilical venous (UV)/maternal plasma (MP) ratio (even after multiple-dose oral administration to steady state) does not necessarily reflect fetal drug exposure. In addition, we verified the implementation of this m-f-PBPK model by comparing the predicted UV/MP and fetal/MP AUC ratios with those predicted at steady state after an intravenous infusion. Our simulations yielded novel insights into the quantitative contribution of fetoplacental metabolism and/or placental transport on gestational age-dependent fetal drug exposure. Through sensitivity analyses, we demonstrated that the UV/MP ratio does not measure the extent of fetal drug exposure unless obtained at steady state after an intravenous infusion or when there is little or no fluctuation in MP drug concentrations after multiple-dose oral administration. The proposed m-f-PBPK model can be used to predict fetal exposure to drugs across gestational ages and therefore provide the necessary information to assess the risk of drug toxicity to the fetus.

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

“…Another approach was presented by Zhang et al for compounds crossing the placenta exclusively via passive diffusion . In this case, the fetal‐to‐maternal partition ratio was assumed to equal 1.0.…”

“…Apart from the explicit integration of placental transporters, these models may also benefit from finer representation of fetal physiology. Recently, several repositories have been published that review physiological changes in the fetus, such as organ growth, change in blood flow rates, tissue composition, and drug‐binding protein concentrations . In addition, drug transfer may also be influenced by the pH difference between the fetal and maternal blood.…”

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

“…At that time, different PBPK models for pregnant women were developed in MatLab or as part of Simcyp, GastroPlus, and also in the Open Systems Pharmacology (OSP) software suite which includes the software programs PK‐Sim and MoBi (https://github.com/Open-Systems-Pharmacology/Pregnancy-Models). Some of these models were subsequently used as a basis for further model refinement and/or incorporation of information on system‐specific parameters that were not part of the original model, such as changes in the activity of specific CYP enzymes . Furthermore, a variety of semimechanistic or minimal PBPK models for pregnant women can also be found in the literature .…”

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…described such a feto‐pregnancy‐PBPK model in which a placenta, amniotic fluid compartment, and fetal organs that are relevant to drug disposition were added, the model also took into account typical characteristics of the fetal circulation. Gestational age‐dependent changes in fetal, placental, and maternal physiological parameters during the second half of pregnancy were described using empirically derived polynomial equations . Using the model, the authors elegantly demonstrated that cord to maternal plasma ratios, even at distribution equilibrium, do not indicate fetal drug exposure relative to that in the mother, which is due to the time‐dependent distributional kinetics of drugs across the placenta.…”

“…In addition, they used sensitivity analysis to assess the possible impact of gestational age‐dependent changes in placental metabolism and transport processes on placental transfer. To verify performance of the model for predicting the placental passage of only passively diffusing drugs, the authors populated the model using midazolam as a calibrator drug, and subsequently verified the model by adequately predicting the fetal exposure of two other passively diffusing drugs, theophylline and zidovudine . For antiretroviral agents, similar approaches for incorporating placental transfer and drug disposition in lumped fetal compartments have been described by De Sousa Mendes et al .…”