%0 Journal Article %A Zufei Zhang %A Marjorie Z. Imperial %A Gabriela I. Patilea-Vrana %A Janak Wedagedera %A Lu Gaohua %A Jashvant D. Unadkat %T Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses %D 2017 %R 10.1124/dmd.117.075192 %J Drug Metabolism and Disposition %P dmd.117.075192 %X 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: maternal plasma (UV:MP) ratio (even after multiple oral dose 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:maternal plasma AUC ratios with those predicted at steady-state after an IV infusion. Our simulations yielded novel insights on 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 IV infusion or when there is little or no fluctuation in maternal plasma 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 feus. %U https://dmd.aspetjournals.org/content/dmd/early/2017/06/06/dmd.117.075192.full.pdf