Abstracts

Rationale:
Poor medication adherence is a major contributor to increased mortality and morbidity in patients with chronic diseases. Unfortunately, medication nonadherence is often not addressed in the clinic, and in patients with epilepsy, this may result in inappropriate changes in pharmacotherapy treatment regimens, which could result in worsening of seizure control. Due to ethical concerns, it is impossible to study nonadherence in clinical trials; however, our lab has established a first of its kind, reliable preclinical model to evaluate the effect of anti-seizure medication (ASM) nonadherence on seizure control. Perampanel (PER) is a clinically approved ASM with broad spectrum anti-seizure activity, however, its efficacy has not yet been studied in the context of nonadherence. In order to examine PERs anti-seizure efficacy in this paradigm, we have optimized it’s formulation into rodent chow pellets to be automatically delivered to animals in a novel feeding system. Furthermore, we are currently assessing the oral tolerability of chronic PER dosing before evaluating its anti-seizure profile in an etiologically relevant model of temporal lobe epilepsy (TLE); i.e., the post-status epilepticus (SE) rat.
Method:
PER (0.33 mg/g) was formulated in rodent chow (Bio-Serv, F7762), formed into approximately 1 g pellets, and processed for analysis on a Water’s Xevo TQ-s mass spectrometer to determine the inter- and intra-pellet distribution of PER content. In vivo studies utilized our novel automated feeder system to administer placebo pellets (q.i.d., p.o) to naïve adult male Sprague-Dawley rats over 3 weeks to confirm a daily feeding paradigm that supports normal growth rates. A separate cohort of naïve animals are currently undergoing behavioral studies to determine the oral tolerability of PER administration when administered at doses ranging from 5-20 mg/kg/day (q.i.d., p.o.).
Results:
Animals consumed ~95% of placebo pellets when administered in a feeding paradigm of 60 g/kg/day, which supported normal growth rates. PER pellets formulated in-house were consistent in size (~1g ± 0.04g) and determined to have a uniform distribution of PER within each pellet (%CV: 4), and between different pellets (%CV: 2). PER oral tolerability studies are ongoing and the maximum tolerated dose will then be used for anti-seizure efficacy studies in a nonadherent dosing paradigm in the post-SE rat.
Conclusion:
These formulation and tolerability studies are necessary to establish a dosing paradigm that delivers safe and consistent doses of PER to animals in a controlled manner. With these measures in place, we can reliably determine the effect of variable medication adherence on PER’s anti-seizure efficacy in a rat model of TLE.
Funding:
:Unrestricted grant from Eisai Inc.