Optimizing Betamethasone Therapy for Preventing Respiratory Distress Syndrome in Twin Pregnancy - PROJECT SUMMARY Twin pregnancies account for approximately 3% of all births in the U.S. Twin pregnancies show distinct physiological differences compared to singleton pregnancies that can impact the efficacy and safety of drugs used during pregnancy. Betamethasone is a synthetic corticosteroid that is used in pregnant women who are at risk for preterm delivery to promote fetal lung maturation and to reduce the incidence of respiratory distress syndrome (RDS) in neonates. However, our understanding of the impact of these physiological changes in twin pregnancies on pharmacokinetics and pharmacodynamics and, thus, the efficacy and safety of drugs used in women with pregnancies is currently limited. The primary objective of the proposed project is to narrow this knowledge gap using betamethasone as a prototypical paradigm compound. First, we will develop physiologically-based pharmacokinetic (PBPK) models for twin monochorionic and dichorionic twin pregnancies (Specific Aim #1). We will incorporate pregnancy- specific changes, including the induction of CYP3A4 by elevated 17β-estradiol levels in twin pregnancies. Using clinical data from both singleton and twin pregnancies, we will establish dose-exposure-response relationships for betamethasone and RDS prevention in the fetus through the integrated use of model-based meta-analysis (MBMA) and PBPK modeling and simulation approaches. This will allow us to propose optimal dosing and dose- to-delivery intervals for betamethasone to prevent RDS in twin pregnancies (Specific Aim #2). Our research will support drug label improvement, as the current use of betamethasone in RDS is still off-label. Ultimately, our research will generate quantitative insights into this underrepresented population, refining the dosing strategies for betamethasone and paving the way for safer, more effective treatments for high-risk twin pregnancies.
