Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity

OBJECTIVE Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49–10.44] and 3.71 [0.86–13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight. ABBREVIATIONS AED01, “Pharmacokinetics of Anti-epileptic Drugs in Obese Children and Adolescents” study; BMI, body mass index; CL, clearance; C_max,ss, simulated maximum concentration at steady state; C_min,ss, simulated minimum concentration at steady state; eGFR, estimated glomerular filtration rate; E_MAX, maximal effect of high drug concentrations; FDA, Food and Drug Administration; FFM, fat-free mass; GA, gestational age; HT, body height; KA, absorption rate constant; LBM, lean body mass; NFM, normal fat mass; OFV, objective function value; pcVPCs, prediction corrected visual predictive checks; PK, pharmacokinetics; PNA, postnatal age; PMA, postmenstrual age; POP01, “Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care” study; PopPK, population pharmacokinetics; SCR, serum creatinine; TBW, total body weight; V, volume; WT, body weight.