A Physiologically Based Modeling Approach to Evaluate Intravenous Levetiracetam Dosing in Term and Preterm Neonates

Abstract

Seizures are the most common neurologic emergency in neonates and are associated with significant morbidity and mortality. Current first-line pharmacotherapy, phenobarbital, is associated with serious adverse effects, including impairment of the developing brain. Levetiracetam is a well-tolerated alternative; however, its use is limited because its optimal dosing in neonates remains unknown. Additionally, limited knowledge of levetiracetam pharmacokinetics in neonates, especially preterm neonates, means they generally receive the same weight-based dosing. This may put preterm neonates at risk of increased adverse events or insufficient drug effects. This study developed a physiologically based pharmacokinetic (PBPK) model for levetiracetam in term and preterm neonates to evaluate their pharmacokinetic differences. After accounting for the physiological changes, a 1.56-fold increase in drug tissue distribution was needed to represent the increased volume of distribution of levetiracetam in neonates. In term neonates, scaling renal clearance from children based on estimated glomerular filtration rate required a 61% increase to accurately describe renal clearance. Additionally, allometric scaling to extrapolate metabolic clearance required age-dependent corrections to account for the reduced metabolic clearance. In preterm neonates, extrapolated renal clearance was approximately equal to observed total clearance, suggesting renal clearance as the sole elimination route. Consistently, predicted metabolic clearance approached zero when the postmenstrual age was <37.5 weeks. Our simulations showed that common intravenous levetiracetam dosing regimens resulted in higher plasma concentrations in more premature neonates or those with reduced kidney function. In preterm neonates, these regimens may result in plasma concentrations exceeding toxicity thresholds, indicating a need for lower weight-based dosing.