Physiologically Based Pharmacokinetic Modeling of Caffeine in Preterm Neonates: Influence of Renal Function and Impairment on Dosing.

Currently, the same weight-based caffeine citrate dosing regimen is applied to all neonates. However, due to differences in growth trajectories by gestational age (GA) and altered caffeine elimination in neonates with renal injury, optimal dosing regimens may differ. In this study, we refined the existing physiologically based pharmacokinetic (PBPK) model for caffeine in preterm neonates (GA 25-32 weeks) using Simcyp to evaluate dosing across varying ages and renal function. Real-world data were used to generate weight-for-age growth curves and create virtual preterm populations. CYP1A2 ontogeny model was updated to better reflect the reduced metabolic activity of caffeine in preterm neonates. A 13.7-fold increase in glomerular filtration rate-adjusted renal clearance was needed to match observed data. Additionally, a higher volume of distribution (0.96 L/kg) was required to account for increased body water. The final model was verified using clinical pharmacokinetic data and used to simulate plasma concentration-time profiles. Our simulations showed that more premature neonates (≤28 weeks GA) may require lower weight-based maintenance dosing (8 mg/kg) compared with those with higher GA (10 mg/kg), and may also require an increase in doses after 4-6 weeks of therapy to maintain therapeutic levels. Neonates with significantly reduced renal function (25% of normal) may need a two- to threefold dose reduction. Future studies should aim to define optimal therapeutic targets, as caffeine use continues to expand.