ABSTRACT Dedicated pharmacokinetic (PK) drug-drug interaction (DDI) studies are performed in healthy adult volunteers during drug development. However, dedicated PK DDI studies are rarely performed in infants due to ethical and logistical reasons. This results in the extrapolation of adult drug dosing recommendations that account for the DDI potential to infants despite known age-induced physiological changes that can alter PK and affect the DDI magnitude in infants. Physiologically-based pharmacokinetic (PBPK) models are an ideal tool to characterize PK DDIs in infants because they can account for the DDI mechanism and physiological age-induced changes that affect the DDI magnitude early in life. This proposal will evaluate a systematic approach to PK DDI evaluation in infants using PBPK modeling and real-world data to accelerate the availability of age-appropriate drug dosing recommendations in light of the DDI potential. We will characterize DDIs involving the cytochrome P450 (CYP) 3A substrates midazolam and fentanyl, and the CYP2C9/2C19 substrate phenobarbital, when co-administered with drugs that inhibit their metabolism. We will validate the PBPK model DDI predictions using real-world data collected from infants receiving the drug combinations per standard of care. The PBPK models will then guide drug dosing that accounts for differences in DDI magnitude with age. Once our systematic approach to PBPK model informed DDI evaluation in infants is established, it can be applied to characterize other PK DDIs and accelerate the availability of drug dosing recommendations for infants in light of the DDI potential.