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Background: While physiologically based pharmacokinetic (PBPK) models generally predict pharmacokinetics in pregnant women successfully, the confidence in predicting fetal pharmacokinetics is limited because many parameters affecting placental drug transfer have not been mechanistically accounted for.Objectives: The objectives of this study were to implement different maternal and fetal unbound drug fractions in a PBPK framework; to predict fetal pharmacokinetics of eight drugs in the third trimester; and to quantitatively investigate how alterations in various model parameters affect predicted fetal pharmacokinetics.Methods: The ordinary differential equations of previously developed pregnancy PBPK models for eight drugs (acyclovir, cefuroxime, diazepam, dolutegravir, emtricitabine, metronidazole, ondansetron, and raltegravir) were amended to account for different unbound drug fractions in mother and fetus. Local sensitivity analyses were conducted for various parameters relevant to placental drug transfer, including influx/efflux transfer clearances across the apical and basolateral membrane of the trophoblasts.Results: For the highly-protein bound drugs diazepam, dolutegravir and ondansetron, the lower fraction unbound in the fetus vs. mother affected predicted pharmacokinetics in the umbilical vein by ≥10%. Metronidazole displayed blood flow-limited distribution across the placenta. For all drugs, umbilical vein concentrations were highly sensitive to changes in the apical influx/efflux transfer clearance ratio. Additionally, transfer clearance across the basolateral membrane was a critical parameter for cefuroxime and ondansetron.Conclusion: In healthy pregnancies, differential protein binding characteristics in mother and fetus give rise to minor differences in maternal-fetal drug exposure. Further studies are needed to differentiate passive and active transfer processes across the apical and basolateral trophoblast membrane.

The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.