PBPK Models for Fetal Drug Exposure: A Critical Assessment of Current Approaches and Regulatory Readiness

Abstract

Physiologically based pharmacokinetic (PBPK) modeling has emerged as a critical tool for predicting fetal drug exposure during pregnancy, accounting for the complex interplay of maternal physiological changes and placental transfer mechanisms. This review summarizes the current state of PBPK modeling in maternal‐fetal pharmacology, discussing various modeling approaches, including compartmental structures and mathematical formulations for placental transfer, as well as approaches to parameterize placental drug transfer in humans. Furthermore, a regulatory perspective on the use of maternal‐fetal PBPK models in submissions to the MHRA is provided. Despite advancements, significant gaps remain in understanding the variability of placental drug transfer across gestational stages and the implications of transporter activity. Future research should focus on generating robust clinical data and integrating innovative technologies, such as organ‐on‐a‐chip systems, to enhance model accuracy. Additionally, regulatory acceptance of PBPK models will depend on the establishment of comprehensive validation frameworks. By fostering collaboration between researchers, clinicians, and regulatory bodies, PBPK modeling can advance toward safer therapeutic options for pregnant women and their developing fetuses, ultimately improving maternal‐fetal health outcomes.