Population Pharmacokinetic Analysis of Drug–Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients

Abstract

Background: Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics. Methods: We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time–concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error. Results: A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ. Conclusions: We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice.

Population pharmacokinetics and dosing optimization of perampanel in children with epilepsy: A real‐world study

“…In line with the result from previous model analysis, 23 our study also found that a one‐compartment model with first‐order absorption and elimination could adequately characterize the pharmacokinetic profile of PER. After normalization to a median WT of 30.0 kg, the typical value of CL in our study was .020 L/h/kg, which is marginally higher than values reported in adolescent (.012–.014 L/h/kg) and adult populations (.010–.012 L/h/kg) 24–26 . This may be attributed to differences in the age range and ethnicity of the patients included, and sample size between the studies.…”

“…After normalization to a median WT of 30.0 kg, the typical value of CL in our study was .020 L/h/kg, which is marginally higher than values reported in adolescent (.012-.014 L/h/kg) and adult populations (.010-.012 L/h/kg). [24][25][26] This may be attributed to differences in the age range and ethnicity of the patients included, and sample size between the studies. In this popPK analysis, WT, TBIL, and OXC were identified as influencing factors for the CL of PER.…”

Initial therapeutic target attainment of perampanel in pediatric patients with epilepsy

“…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 ). However, the influence of the enzyme inhibitor AED, valproic acid, was not identified in this study.…”

“…Some studies have shown that PER plasma levels were affected by otherAEDs in routine TDM practice, including carbamazepine, phenobarbital, valproate and topiramate ( Patsalos et al, 2016 ; Contin et al, 2018 ; Silva et al, 2023 ). A recent study indicated that enzyme-inductive AED could increase PER clearance ( Fujita et al, 2022 ). However, it is still unknown whether these drug interactions have impact on PER therapeutic target nonattainment.…”