Modeling and simulation of intravenous levetiracetam pharmacokinetic profiles in children to evaluate dose adaptation rules

SummaryPurposeTo develop a pharmacokinetic model for intravenous levetiracetam in children, based on adult intravenous data and pediatric oral data.MethodsData from two adult Phase-I studies in which levetiracetam was given intravenously were utilized to develop the adult population pharmacokinetic two-compartment intravenous model. After model qualification, combination with an existing pediatric one-compartment oral population pharmacokinetic model enabled simulation of twice-daily intravenous infusions of levetiracetam in children. Median and 90% confidence intervals for Ctrough, Cmax (end of infusion) and AUCτ were simulated for 2000 children and compared to the values observed in adults.ResultsThe population pharmacokinetic two-compartment model successfully described intravenous levetiracetam pharmacokinetics in healthy adults. After combination with the oral pediatric population model, steady-state concentrations at the end of 15-, 30- and 60 min b.i.d. levetiracetam intravenous infusions in children were predicted to be 29–41, 17–24 and 6–13% higher than those observed after oral dosing of 30 mg/kg b.i.d. Concentrations returned to the range of oral exposures within 1 h after the infusion peak. The combined model predicted that steady-state peak plasma concentrations and AUCτ in children receiving 30 mg/kg twice daily as 15 min intravenous infusions were within the range of predicted and observed Cmax,ss and AUCτ values of adults receiving 15 min intravenous infusions of 1500 mg levetiracetam.ConclusionsThe simulations suggest that levetiracetam may be administered intravenously in children as 15 min infusions.