The mainstay of treatment for infants with hypoxic-ischemic encephalopathy (HIE) is cooling. Caffeine may be an important adjunct to cooling and provide neuroprotection via its anti-inflammatory and anti-oxidative properties. This study aimed to characterize caffeine pharmacokinetics in term infants with HIE receiving cooling. In this phase 1, dose-escalating study, enrolled infants received IV caffeine 20 mg/kg followed by up to two daily doses of 5 or 10 mg/kg. A population pharmacokinetic analysis was performed using NONMEM (v7.5). The effects of clinical covariates, including cooling, on pharmacokinetic parameters were evaluated. Dosing simulations were performed to evaluate the percentage of plasma exposures in the reference range (15-25 mg/L). Seventeen infants were included in model development. A one-compartment model best fit the data. Population clearance was 0.445 L/h/70 kg and volume of distribution was 87.1 L/70 kg. Current dosing regimens (20 mg/kg followed by 5 mg/kg) resulted in 89.5% of infants having at least one simulated exposure below the reference range across the dosing interval. Dosing regimens of 30 mg/kg followed by 5 or 10 mg/kg were predicted to result in more than half of infants achieving simulated exposures in the reference range, with ≤20% of infants having simulated exposures in the toxic range (>
46 mg/L). Term infants with HIE had similar weight-normalized clearance but higher weight-normalized volume of distribution compared to prior studies in preterm infants without HIE or cooling. While exposure targets for neuroprotection in HIE are unknown, this phase 1 study suggests alternate dosing strategies should be considered in future studies.