Physiologically based pharmacokinetic modeling of Acetaminophen in a preterm neonate population

Extremely preterm neonates are a pharmacologically vulnerable group due to their immature organ function and rapid developmental changes, which complicate optimal drug dosing. This thesis introduces a comprehensive physiologically based pharmacokinetic (PBPK) model for acetaminophen (APAP) tailored to this population, incorporating mechanistic ontogeny equations for key sulfotransferase (SULT) enzymes SULT1A1, SULT1A3, SULT1B1, and SULT2A1 developed from a unique dataset of pediatric liver samples. The PBPK model was calibrated and validated using observed pharmacokinetic data from neonates, infants, and children, demonstrating high predictive accuracy across developmental stages. By applying virtual twin simulations, the model was used on a nationwide children's hospital clinical dataset of extremely preterm neonates treated with intravenous APAP for patent ductus arteriosus (PDA) closure. The simulation results for Cmax and AUC closely matched observed data across various dosing regimens (15, 20, and 25 mg/kg). Ordinal logistic regression showed that gestational age and birth weight, rather than drug exposure alone, were significant predictors of therapeutic success, emphasizing the complex exposure-response relationship. Sensitivity analysis of SULT2A1 ontogeny indicated that a ±50% change could influence systemic exposure by up to 20%, highlighting the clinical importance of developmental enzyme activity in dosing choices. Compared to traditional population PK models, this PBPK framework provides a mechanistically grounded, individualized approach to optimizing therapy in preterm neonates. The findings support deploying model-informed precision dosing strategies in neonatal intensive care units (NICUs), with potential applications across different age groups and drug types. This work advances pediatric systems pharmacology by delivering a validated tool for safer and more effective use of acetaminophen in the most vulnerable neonatal populations.