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

• Published in: Drug metabolism and disposition Vol. 45; no. 8; pp. 920 - 938
• Main Authors: Zhang, Zufei, Imperial, Marjorie Z., Patilea-Vrana, Gabriela I., Wedagedera, Janak, Gaohua, Lu, Unadkat, Jashvant D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017; American Society for Pharmacology and Experimental Therapeutics, Inc; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Age; Computer simulation; Drug dosages; Ethics; Exposure; Female; Fetus - metabolism; Fetuses; Gestational Age; Humans; Intravenous administration; Intravenous infusion; Maternal Exposure - adverse effects; Maternal-Fetal Exchange - physiology; Mathematical models; Metabolism; Models, Biological; Oral administration; Pharmaceutical Preparations - metabolism; Pharmacokinetics; Pharmacology; Placenta; Placenta - metabolism; Pregnancy; Risk assessment; Sensitivity analysis; Steady state; Toxicity; Transport; Variation; CLPD; steady stateinf; F/M; PBPK; C-T; CLPD,u; P/M; m-f-PBPK; m-PBPK; CLMP; CLm0; ka; GA; Fa; AUCp; AUCm; Fg; UV; MP; P-gp; AUCf; CLf0; HIV; CLp0; Vss; Cmax,f; CLPM; PK
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.117.075192

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.