Retrospective Population Pharmacokinetic Analysis of Levetiracetam in Children and??Adolescents with Epilepsy

Abstract

To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults. Nonlinear mixed-effects modelling was used to analyse pooled data collected from 228 children with epilepsy aged 3 months to 18 years in five trials of adjunctive levetiracetam therapy. Simulations were used to identify dosing regimens achieving levetiracetam steady-state peak and trough plasma concentrations similar to those attained in adults receiving the recommended starting dose for adjunctive therapy (500 mg twice daily). The covariates considered for inclusion in the base model were age, bodyweight, gender, race, body surface area (BSA), body mass index (BMI), creatinine clearance (CL(CR)), levetiracetam dose, concomitant antiepileptic drug (AED) by category (neutral, enzyme inducer, inhibitor, combination of inducer and inhibitor), and benzodiazepines. A one-compartment model with first-order absorption and elimination best characterized the data. The following significant covariates were identified: (i) age on the absorption rate constant (k(a)); (ii) bodyweight, dose, CL(CR) and concomitant enzyme-inducing AED on plasma oral clearance (CL/F); and (iii) bodyweight on the apparent volume of distribution after oral administration (V(d)/F). The main explanatory covariates were age on k(a), bodyweight on CL/F and V(d)/F, and enzyme-inducing AED on CL/F, of which bodyweight was the most influential covariate. Dosing can be carried out with either 10 mg/kg of oral solution twice daily in children weighing <50 kg and a 500-mg tablet twice daily in those weighing >50 kg or, when patients favour a solid formulation, 10 mg/kg of oral solution twice daily in children weighing <20 kg, a 250-mg tablet twice daily in those weighing 20-40 kg, and a 500-mg tablet twice daily in those weighing >40 kg. All of these doses achieved steady-state peak and trough plasma concentrations similar to those observed in adults following the recommended starting dose for adjunctive therapy (500 mg twice daily). The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.