Utility of a physiologically-based pharmacokinetic model for investigating time-dependent variability in the fetal-to-maternal plasma concentration ratio of digoxin

The purpose of this study was to elucidate the mechanisms underlying the wide variability in fetal-to-maternal (F/M) concentration ratios of digoxin by comprehensively characterizing maternal and fetal pharmacokinetics using a physiologically based pharmacokinetic (PBPK) model that explicitly incorporates pregnant women, the placenta, and the fetus, with particular emphasis on placental transfer processes and time-dependent concentration dynamics. Maternal–fetal digoxin pharmacokinetics were simulated using a maternal–placental–fetal PBPK model implemented in Simcyp™. Placental transfer was described by separating passive diffusion, informed by human placental perfusion data, and P-gp–mediated active efflux scaled from in vitro data using quantitative proteomics. Gestation-dependent fetal renal excretion and amniotic fluid pathways were incorporated. Model predictions were verified against reported clinical maternal pharmacokinetic data. Global sensitivity analysis and pathway contribution analysis were performed to identify key determinants of fetal exposure. Placental P-gp activity selectively influenced fetal digoxin exposure without affecting maternal pharmacokinetics, and model predictions were consistent with clinical maternal data. Fetal exposure was primarily governed by direct placental transfer, whereas amniotic fluid–mediated pathways contributed only minimally. Although F/M (AUC ratio) remained relatively stable, instantaneous F/M values exhibited marked time-dependent variability. These findings indicate that a single time-point F/M may not adequately reflect fetal exposure for digoxin. Time-resolved PBPK analyses provide a mechanistic framework to complement conventional F/M-based assessments of maternal–fetal drug exposure.