Perampanel Pharmacokinetics in Children: Correlation of Dose With Serum Concentrations

Abstract

Enzyme-inducing antiseizure drugs taken concomitantly with perampanel are known to influence perampanel serum concentrations. In this study, we examined perampanel dosage, serum concentrations, and the effect of concomitant enzyme-inducing antiseizure drugs in children for a 3-year period. A retrospective chart review determined patient age, weight, perampanel serum concentration and prescribed dose, and concomitant drugs. Of 87 patients included in the study, 41 were prescribed an enzyme-inducing antiseizure drug. Although perampanel dosage did not differ between patients prescribed/not prescribed enzyme-inducing antiseizure drugs, serum concentrations were significantly lower in patients taking enzyme-inducing antiseizure drugs (average serum concentration for the enzyme-inducing antiseizure drug group was still above the previously reported efficacious serum concentration of 70 ng/mL). Although perampanel serum concentrations are negatively influenced by enzyme-inducing antiseizure drugs in children, it is likely that efficacy would be improved in patients not concomitantly prescribed enzyme-inducing antiseizure drugs because pediatric perampanel dosing is similar to that reported in prior adult efficacy trials.

Initial therapeutic target attainment of perampanel in pediatric patients with epilepsy

“…Concomitant use of carbamazepine and oxcarbazepine was negatively correlated to PER C/D in our study. This is in accordance with previous reports that the concomitant use of enzyme-inducing AEDs could result in lower PER concentrations or C/D, both in children and adults ( Patsalos et al, 2016 ; Gaudio et al, 2019 ; Ikemoto et al, 2019 ; Ishikawa et al, 2019 ). Carbamazepine could increase the clearance of PER in a population pharmacokinetic analysis ( Fujita et al, 2022 ).…”

LC-MS/MS assay for the therapeutic drug monitoring of perampanel in children with drug-resistant epilepsy

“…5B, no significant correlation (r 5 0.430) was found between PER concentrations and weight-adjusted dose. However, the correlation could be significantly improved if we separate patients into concomitant enzyme-inducing ASMs groups (r 5 0.628) and concomitant non-enzyme-inducing ASMs groups (r 5 0.624), which was consistent with previous studies in children and adults [5,6,8]. What's more, the concomitant use of enzyme-inducing ASMs resulted in a marked decrease of the regression equation slope (2254.2 versus 1037.8), which was also in line with previous studies [6,26].…”

“…Several studies have confirmed the significant association between dose-exposure (plasma concentration)-effectadverse events (AEs) of PER in adult and pediatric patients with epilepsy [5][6][7][8][9], but the reference concentration ranges of PER are still controversial [5,10]. On the other hand, PER is substantially (approximately 95%) bound to plasma proteins [11] and metabolized by cytochrome P450 (CYP450) enzyme, especially for CYP3A4 [9,[12][13][14], which partly determine the efficacy and AEs related to the plasma concentration of PER [5].…”

Pharmacokinetics, tolerability, and clinical effectiveness of perampanel in Japanese patients with epilepsy

“…Previous studies showed that concomitant use of PHT or CBZ leads to a reduction in the serum concentration of perampanel by 50%-70% [2,3]. Recently, perampanel was approved for clinical use in patients aged under 12 years, and its concentration was found to be significantly impacted by inducers in this population [4][5][6]. Therapeutic drug monitoring (TDM) for perampanel can be helpful for predicting the extent of drug interactions and adjusting the dose of perampanel in patients of all ages.…”