Abstracts

Rationale: Poor medication adherence is a major contributor to increased morbidity and mortality, however it is often under-addressed in clinical practice. For patients with epilepsy, this may result in worse seizure control. Due to ethical concerns, it is impossible to study the impact of medication nonadherence in clinical trials; however, our lab has established a first of its kind, reliable preclinical animal model to evaluate the effect of anti-seizure medication (ASM) nonadherence on seizure control. Perampanel (PER) is a clinically approved broad spectrum ASM, however, its efficacy has not yet been studied in this context. Using an etiologically relevant model of temporal lobe epilepsy (TLE); i.e., the post-status epilepticus (SE) rat, we investigated PER’s antiseizure efficacy following chronic oral ASM administration in a fully adherent and variably nonadherent paradigm.

Methods: A repeated low-dose kainic acid (KA)-induced SE paradigm was used to induce chronic epilepsy in adult male Sprague-Dawley rats. Following video-EEG confirmation of spontaneous recurring seizures, animals were enrolled on placebo (PCBO) chow for 4 weeks to establish their baseline seizure frequency and burden. Animals were then randomly assigned to the maximally tolerated dose of PER (2.5 mg/kg q.i.d, p.o.) either 100% or randomly 50% of the time during a 4-week treatment phase. PER plasma concentrations were analyzed weekly using a Water’s Xevo TQ-s mass spectrometer. Seizure behavior was scored using the Racine scale and changes in overall seizure frequency and seizure burden were identified. Patterns of medication nonadherence were analyzed to determine the temporal relationship between a missed dose and of the occurrence of a seizure.

Results: Early data suggests that complete adherence (100%) to PER results in an average reduction in seizure frequency of ~46%, with ~30% of animals exhibiting complete seizure freedom. While not statistically significant, variable adherence (50%) to PER results in a worsening of an animal’s seizure burden, averaging ~196% increase in seizure frequency. Plasma concentrations of PER were significantly elevated in the animals receiving PER 100% of the time compared the the 50% group over the entire 4-week treatment intervention phase. Furthermore, preliminary analyses suggest that the relationship between a missed dose and a seizure cannot be explained by the pharmacokinetics of the drug alone.

Conclusions: This study demonstrates that PER is an effective ASM in the post-SE rat model of chronic epilepsy. Unsurprisingly, PER was more effective in the 100% adherence paradigm compared to the 50% adherence paradigm, which is supported by elevated and sustained PER plasma concentrations in these animals. However, more detailed analysis of the relationship between a missed dose and seizure suggests that PER pharmacokinetics alone cannot explain patterns of breakthrough seizures in the setting of medication nonadherence.

Funding: Please list any funding that was received in support of this abstract.: Unrestricted grant from Eisai Inc.