Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population

Abstract

Background: Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity.

Objective: This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework.

Methods: A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim^® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models.

Results: Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature.

Conclusions: PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.

Fig. 1

For single dose: Visual inspection of simulated levetiracetam plasma concentration vs time profiles in neonates (IV infusion, Panels A and B) and children younger than 2 years (PO solution, Panels C and D) after a single dose of levetiracetam 20 mg/kg with respect to observed data reported by Blonk et al. [43] and Glauser et al.[20]. Observed mean plasma concentration vs time data (circles) were compared with the simulated median (solid line) concentration data and 90% prediction interval (shaded region) in the virtual population (n = 1000). For multiple dose: Visual inspection of simulated of levetiracetam plasma concentration vs time profiles in neonates after multiple doses of oral (E) and IV (F) levetiracetam in neonates with respect to observed data reported by Pillay-Fuentes Lorente et al. [16] and Sharpe et al. [17]. Observed mean plasma concentration vs time data (circles) were compared with the simulated median (solid line) concentration data and 90% prediction interval (shaded region) in the virtual population (n = 1000). Red shaded region represents higher dose (30–50 mg/kg/day) and green shaded region represents lower dose (10–20 mg/kg/day) administered to subjects in the PK studies.

Fig. 2

Average fold error of predicted to observed levetiracetam plasma concentrations compared across extended body mass index (BMI) percentile. Extended BMI percentile was calculated as BMI divided by the 95th BMI percentile for a subject’s age and sex. Dashed lines represent the 2-fold error range. Figure includes comparison for 72 children, 1 outlier value (AFE = 15.30, Extended BMI Percentile = 111.6%) was removed to improve data visualization.

Fig. 3

Simulated body weight-normalized clearance of levetiracetam in children older than 2 years stratified across non-overweight, overweight, Class 1 obesity, Class 2 obesity, and Class 3 obesity status. Clearance was calculated as dose/AUC_tDlast_minus_1_tDlast. AUCt_Dlast_minus_1_tDlast was calculated as AUC in the interval between the (last - 1) application and the last application at steady-state. For pediatric populations, Non-overweight: BMI ≥ 5th percentile and BMI < 85th percentile; Overweight: BMI ≥ 85th percentile and BMI < 95th percentile; Class I obesity: BMI ≥ 95th percentile and BMI < 120% of the 95th percentile; Class II obesity: BMI ≥ 120% of the 95th percentile and BMI < 140% of the 95th percentile; Class III obesity: BMI ≥ 140% of the 95th percentile. Boxes represent the median and interquartile range (IQR), whiskers extend to 1.5*IQR, and black circles indicate outliers. Under each weight status, N represents the number of individuals from the AED01 and POP01 studies who were included in the analysis.

Fig. 4

Comparison of body-weight normalized levetiracetam clearance in a virtual population of children older than 2 years with obesity using the final PBPK model (black open circles) and individual estimates of body weight-normalized clearance obtained from a previously published population pharmacokinetic (popPK) analysis (red solid circles). PopPK estimates are in children with obesity from the AED01 and POP01 studies. The blue line indicates the smooth line based on a generalized additive model using the geom_smooth function in the R package ggplot2.