Comparison of Metformin PBPK Models Incorporating Placental Transfer to Predict Fetal and Maternal Exposure

Physiologically based pharmacokinetic (PBPK) modeling of placental drug transfer is an evolving tool for predicting fetal drug exposure. In this study, a pregnancy-specific metformin PBPK model was developed, and the following four approaches were evaluated to predict metformin placental transfer: (1) perfusion-limited model, and permeability-limited models using (2) ex vivo cotyledon open system apparent clearance, (3) ex vivo cotyledon closed system data fit to a three-compartment model to estimate clearance, and (4) active transport kinetics and passive clearance. Simulated metformin maternal plasma concentrations (MPCs) and umbilical cord venous plasma concentrations (UCCs) were compared to observed in vivo data from subjects with gestational diabetes mellitus taking metformin 500 mg twice daily. Model selection criteria were determined by the percentage of observed clinical data falling within the 5th to 95th percentiles of the simulated population. Among the approaches, the model that included passive permeability and in vitro intrinsic transporter clearances (Approach 4) best described placental metformin transfer, with 92% of UCCs falling within the 5th to 95th percentiles of the simulated population. Furthermore, maternal uptake transport had the largest influence on predicted UCCs. A two-fold increase in maternal uptake transport increased the predicted population mean UCC C_max by 97%, whereas a 0.5-fold decrease resulted in a 49% decrease in UCC C_max. This refined PBPK model offers a valuable framework for predicting placental transfer and fetal exposure of metformin when placental transporters are altered throughout pregnancy and/or with pathological conditions.