Pharmacometrics in obstetrics and maternal–fetal medicine research: Bridging gaps in maternal and fetal pharmacology

[...]PBPK models have effectively predicted maternal and fetal drug exposure for medications like nifedipine, allowing for safe management of preterm labor and pregnancy-induced hypertension.5 Additionally, PopPK approaches have been employed to optimize dosing and to identify key covariates affecting drug disposition for magnesium sulfate administration for seizure prophylaxis in pre-eclampsia, considering factors such as altered plasma protein binding, volume of distribution, and clearance.6 However, there is limited data on the application of pharmacometrics in many other pregnancy-specific diseases, including intrahepatic cholestasis of pregnancy, HELLP syndrome, hyperemesis gravidarum, placental abruption, placenta previa, and eclampsia. MATERNAL AND FETAL PBPK MODELS Maternal PBPK models have evolved significantly to describe gestational-dependent changes across trimesters, enhancing our understanding of how predicted maternal drug exposure correlates with observed outcomes and facilitating more precise and safer dosing regimens.7 However, further refinement is needed to address gaps in predicting drug interactions and to account for understudied metabolic pathways and elimination routes in pregnancy. Parameter Current challenge Future approach/improvement Limited Clinical Data Pregnant women are often excluded from clinical trials, resulting in limited drug safety and efficacy data Leverage real-world data from pregnancy registries and post-marketing studies to enrich data collection Dynamic physiological changes in pregnancy Pregnancy induces rapid physiological changes across trimesters (e.g., increased plasma volume, altered enzyme activity) that affect drug pharmacokinetics Develop gestational age-specific models (1–42 weeks of gestation) that simulate changes in physiology and drug metabolism Fetal and placental drug transfer Drug distribution within the placenta and fetal organs is poorly understood, limiting accurate prediction of fetal exposure Continue to develop multicomplex-compartment gestational age-specific fetal models to capture organ-specific drug concentrations, including the liver, brain, and kidneys Metabolic enzyme changes While pregnancy-specific changes to the activity of CYP3A4 and CYP2D6 and their effects on drug metabolism and clearance are known, changes to the activity of several other key enzymes require further study Future pharmacometric models should integrate the effects of less-studied enzymes alongside CYP3A4 and C