(W-038) Development of a Physiologically-Based Pharmacokinetic (PBPK) Model for Caffeine in Pregnancy: Evaluating Neonatal Transfer

Sara Quinney, Phd – Professor, Indiana University School of Medicine; Edgardo Szyld, MD, MS – Professor of Pediatrics, Indiana University School of Medicine; Anna Thomas, MD – Assistant Professor of Clinical Pediatrics, Indiana University School of Medicine; Syed Zaidi, Phd – Postdoctoral Fellow, Indiana University School of Medicine

Objectives: Caffeine is extensively used in neonatal intensive care units (NICUs) to treat and prevent bronchopulmonary dysplasia (BPD) and neurodevelopmental insufficiency (NDI) in premature infants. It effectively reduces the duration of respiratory assistance needed by stimulating spontaneous breathing through adenosine antagonism. Moderate caffeine consumption (less than 200 mg per day) during pregnancy does not appear to be a major contributing factor in miscarriage or preterm birth [1]. Currently, a loading dose of 20 mg/kg of caffeine citrate is administered within the first 6 hours of life, followed by a maintenance dose of 5 mg/kg every 24 hours until approximately 34 weeks of gestational age. Therapeutic plasma concentrations range from 2-20 mg/L.Concentrations as high as 90 mg/L show only transient adverse effects in preterm infants [2]. We hypothesize that maternal administration of caffeine during labor will provide earlier dosing to the neonate. This study aims to develop a physiologically-based pharmacokinetic (PBPK) model to evaluate the transfer of caffeine from pregnant women to their neonates.

Methods: We developed and validated three caffeine PBPK models in Simcyp v23: a non-pregnant model for validation purposes, a pregnant model to predict feto-placental concentrations and a preterm model to predict caffeine plasma concentrations in neonates. The default Simcyp caffeine drug file was modified by adjusting logP and pKa based on data from DrugBank.

Results: This led to a more accurate prediction of absorption. We successfully validated and simulated the pharmacokinetic profiles of caffeine across the three models. Our simulations determined that administering caffeine to pregnant individuals in the third trimester at doses of 120-150 mg every 12 hours resulted in feto-placental concentrations of 5.8-8.6 mg/L, with a neonatal half-life of approximately 7 hours.

Conclusions: This dosage regimen ensures therapeutic levels in the preterm infant at delivery. This approach has the potential to optimize neonatal outcomes by providing an alternative to direct neonatal caffeine administration.

Citations: 1. Glade, M.J., Caffeine—not just a stimulant. Nutrition, 2010. 26(10): p. 932-938. 2. Aranda, J.V. and K.D. Beharry. Pharmacokinetics, pharmacodynamics and metabolism of caffeine in newborns. in Seminars in Fetal and Neonatal Medicine. 2020. Elsevier.