Maternal–placental–fetal physiologically based pharmacokinetic modeling: current approaches and future perspectives

INTRODUCTION: Fetal drug exposure is governed by maternal, placental, and fetal pharmacokinetic processes, among which placental drug transfer plays a central role. However, clinical data in pregnant populations remain limited, creating uncertainty in balancing maternal treatment needs with potential fetal risk. AREAS COVERED: Maternal-placental-fetal physiologically-based pharmacokinetic (PBPK) models provide a mechanistic framework to predict maternal and fetal exposure. This review summarizes the key placental physiological determinants of drug transfer and outlines the current landscape of maternal-placental-fetal PBPK models, including model structures, parameterization strategies, and applications in fetal exposure prediction and exposure-based risk assessment. Strengths and limitations of different data sources were also reviewed, including in vitro, ex vivo, and in vivo data. A PubMed literature search was conducted, with the final search completed on 10 September 2026, to identify relevant maternal-placental-fetal PBPK studies. EXPERT OPINION: Based on perspectives from clinical obstetrics and PBPK modeling, we highlight the need for standardized modeling practices, improved integration of experimental data, transparent characterization of uncertainty, and clinically interpretable model outputs to support medication decision-making during pregnancy. Our goal is to support individualized risk-benefit assessment during pregnancy and inform both clinical practice and regulatory decision-making.