Mechanistic Prediction of Maternal, Fetal, and Amniotic Fluid Betamethasone Concentrations to Support Dosing Optimization in Pregnancy

Abstract

Respiratory distress syndrome (RDS) remains a major cause of neonatal mortality following premature birth. Antenatal betamethasone is the standard of care to accelerate fetal lung maturation and improve neonatal outcomes; however, current dosing recommendations assume uniform maternal and fetal exposure across pregnancies. Gestational age (GA)-dependent physiological changes and maternal obesity may alter betamethasone disposition and fetal exposure. This study developed a maternal–fetal physiologically based pharmacokinetic (m-f-PBPK) model to quantify the effects of GA and maternal obesity on betamethasone exposure and evaluate current dosing recommendations between 24 and 34 gestational weeks. The m-f-PBPK model incorporated maternal CYP3A-mediated metabolism, placental passive diffusion and active efflux via P-glycoprotein (P-gp), placental metabolic clearance, GA-dependent physiology, and formulation-specific release rates of betamethasone phosphate and acetate. Model performance was evaluated using maternal and fetal exposure metrics across gestation. At GA 30 weeks in non-obese pregnancies, placental metabolic clearance contributed approximately 17% of maternal clearance, whereas fetal hepatic metabolism accounted for only 2.4%. Maternal obesity decreased maternal and fetal exposure by approximately 9%, while morbid obesity reduced exposure by 23%. Simulated fetal concentrations remained above the proposed pre-clinical-derived surrogate marker of 2 ng/mL for a median duration of 38-40 h in non-obese, 37.5-39 h in obese, and 30-32 h in morbidly obese populations. This m-f-PBPK model successfully characterized maternal–fetal pharmacokinetics and provides a mechanistic basis for understanding betamethasone fetal exposure across GAs with and without maternal obesity, supporting optimization of antenatal corticosteroid therapy.