TY - JOUR T1 - Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.075192 SP - dmd.117.075192 AU - Zufei Zhang AU - Marjorie Z. Imperial AU - Gabriela I. Patilea-Vrana AU - Janak Wedagedera AU - Lu Gaohua AU - Jashvant D. Unadkat Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/06/06/dmd.117.075192.abstract N2 - 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. ER -