PT-018 - OPTIMIZATION OF THE BETAMETHASONE DOSING REGIMEN DURING PREGNANCY: A COMBINED PLACENTA PERFUSION AND PREGNANCY PBPK MODELLING APPROACH.

J. van der Heijden¹, H. van Hove¹, N. van Elst¹, P. van den broek¹, S. de Wildt^1,2, R. Greupink¹; ¹Radboud University Medical Center, Nijmegen, The Netherlands, ²Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Betamethasone (BETA) is standard care for women at risk of preterm delivery to prevent fetal respiratory distress syndrome. Maintaining a fetal plasma concentration (conc.) >1 ng/ml for 48 hours (h) is considered sufficient for lung maturation. The current dosing regimen of 2 intramuscular (IM) doses of 11.4 mg 24h apart, results in excessive fetal conc., not further contributing to lung maturation but associated with toxicities. We now aim to optimize maternal BETA dosing via pregnancy physiologically-based pharmacokinetic (p-PBPK) modeling.

Methods: P-PBPK modeling for alternative BETA regimens was performed in Simcyp (100 subjects, 28 wks gestation). Performance of the model was first verified against clinical data in non-pregnant subjects, extended with placental transfer parameters, and verified against maternal and fetal clinical data for the standard dose. Placenta perfusion experiments (n=3) were performed to derive placental transfer clearances for parametrization of the placental transfer model for BETA in Simcyp.

Results: The compound model adequately predicted plasma exposure in non-pregnant individuals. BETA intrinsic unbound clearance values for maternal placenta uptake and efflux were 14.7 and 5.7 mL/min, and fetal placenta uptake and efflux values were 8.0 and 1.7 mL/min, respectively. The extended model correctly predicted maternal and fetal plasma conc. for the standard dosing regimen. Exploration of alternative dosages indicated that 3 IM doses of 5.7 mg BETA every 18h, results in lower fetal peak conc. (14.0 vs. 23.9 ng/ml) while 95% of simulated individuals are still maintained for 48h above the minimal exposure target.

Conclusion: Combining p-PBPK modeling with placenta perfusion data provides directions for improved BETA dosing during pregnancy.