Perampanel's forgiveness factor in a variable medication adherence paradigm in a rat model of chronic epilepsy

Abstract

Background: Poor medication adherence contributes to increased morbidity and mortality in patients with epilepsy and may be under-addressed in clinical practice. Ethical concerns make it impossible to study the impact of medication nonadherence in clinical trials, but our previous work emphasizes the importance of using preclinical approaches to address these questions. With over 30 clinically available antiseizure medicines (ASM's), it remains an important question to understand the relationship between poor adherence and seizure incidence across mechanistically distinct ASM's, including the broad-spectrum ASM, perampanel (PER).

Methods: We formulated PER into chow pellets to deliver to rats in a 100% fully adherent or 50% variable nonadherent paradigm via our novel automated medication-in-food delivery system. Chronic oral dosing was initiated in male rats with chronic epilepsy while monitoring 24/7 for videoEEG evidence of seizures during a 4-week placebo baseline and 4-week treatment phase. PER concentrations were monitored in plasma at 1-week intervals and correlated with degree of seizure control. The relationship between missed doses and extended patterns of nonadherence were correlated with breakthrough seizures.

Results: Fully adherent rats demonstrated a median reduction in seizure frequency of 50%, whereas nonadherent rats had a median increase of 54%. Plasma concentrations of PER were stable over the 4-week treatment period in both fully adherent and nonadherent groups, with levels being twice as high in fully adherent animals. There was no correlation between a single missed dose or series of missed doses and the incidence of breakthrough seizures. However, those animals in the nonadherent group that received PER for every meal during a 24-h period had a reduced likelihood of seizure incidence.

Conclusions: If our preclinical data is supported in the clinic, PER's favorable pharmacokinetic profile in humans, combined with a lowered risk of breakthrough seizures suggests that it may provide a certain forgiveness factor if a dose is missed within a 24-h window.

Keywords: Adherence; Antiseizure medicine; Breakthrough seizures; Epilepsy; Perampanel.

Fig. 1

Novel formulation methods for drug-in-food generates consistent and uniform PER pellets. A Representative sample of 1 g PCBO pellets formulated in-house using a commercially available tablet press (TDP5, LFA Machines). Each data point represents a single pellet, n = 50 pellets. B, C Representative chromatogram for a 5 ng/ml calibrator sample (B) and subject sample (C). D PER content within and across a random sample of 10 individual food pellets (A–J). Each dot represents the PER content in ¼ of a pellet, with the line indicating mean value for each pellet. No significant differences between inter-pellet PER content as determined by one-way ANOVA

Fig. 2

Experimental paradigm for measuring PER efficacy in a preclinical nonadherence paradigm. A Adult male Sprague Dawley rats (150–200 g) underwent repeated low dose kainic acid (KA)-induced status epilepticus (SE). Approximately 3–4 weeks following cessation of SE, rats were implanted with cortical EEG electrodes and allowed to fully recover before starting on PCBO chow at 60 g/kg/day (15 g/kg, q.i.d. p.o.). Baseline seizure frequency, burden and severity were recorded for 4 weeks; upon reaching an average > 1 Racine stage 3 or higher seizure/week animals randomly assigned to receive PER 100% of the time (average daily dose: 10 mg/kg/day) or randomly 50% of the time (average daily dose: 5 mg/kg/day) for a 4-week treatment phase. B Schematic depicting meal delivery over the course of a week (q.i.d. × 7 days) for 50% nonadherent treatment group. Red dots indicate medicated meal, black dot represents placebo meal

Fig. 3

Full adherence to PER results in better seizure control than 50% variable nonadherence. A Representative plot demonstrating relationship between medication schedule (red & black dots) and seizure occurrence (gray dots) in three representative animals in the 100% (top) and 50% (bottom) adherence groups over baseline (week 1–4) and treatment periods (week 5–8). B Cumulative seizure burden in the 4-week baseline (PCBO) and 4-week treatment phases for 50% (teal) and 100% (gray) animals. Seizure burden = total sum of behavioral seizure scores. Data presented as mean ± SEM, PER: n = 10 (100%, gray), 12 (50%, blue); ***Significant time × treatment interaction (p < 0.001) as determined by repeated measures 2-way ANOVA with Geisser–Greenhouse correction. C Average daily seizure burden for individual rats during baseline (open circles) and intervention (closed circles) phase. Each dot represents single animal. Data not statistically significant at p < 0.05 as determined by 2-way ANOVA (top). D Normalized change in seizure burden compared to baseline in 100% (gray) and 50% (teal) adherent rats. Data presented as median ± 95% CI. *p < 0.05 as determined by two-tailed Mann–Whitney test

Fig. 4

Overall degree of seizure control with PER is likely dose dependent. A Average weekly pellet consumption for animals in 100% group (black) and 50% adherent group (teal) during baseline (weeks 1–4) and treatment (weeks 5–8) periods. Data presented as mean ± SEM; n: 100% = 10; 50% = 12 animals). **Significant effect of time (p < 0.01) but no main effect of treatment (p = 0.7120) as determined by mixed effects model with Geisser–Greenhouse correction. B PER plasma concentrations at 1, 2, and 4 weeks following the start of PER chow in 100% (black) and 50% (teal) adherent groups. Data presented as mean ± SEM. *Significant effect if treatment at p < 0.05 as determined by mixed-effects model with Geisser–Greenhouse correction. C Spearman correlations for the relationship between the average pellet consumption and PER plasma concentrations for each animal over the 4-week treatment period in 100% (black) and 50% (teal) adherence groups. Each dot represents single animal. D Spearman correlation for the relationship between the change in seizure frequency (compared to baseline) and average PER plasma concentration for each animal in 100% and 50% adherence groups across the 4-week treatment period. *Significantly different at p < 0.05

Fig. 5

24-h periods of nonadherence is not associated with increased risk of breakthrough seizures. A Calculated odds ratio for the relationship between individual patterns of PER nonadherence in a 24 h window (y-axis) and incidence of a seizure (x-axis). Black: PCBO; Red: PER. Data presented as the odds ratio ± 95% CI. Any CI that does not cross one indicates a significant relationship between a specific meal pattern and seizure incidence as determined by two-tailed Chi-Square analysis. n = 206 seizure events across 12 animals. B Odds ratios computed for the relationship between patterns of acute adherence (y-axis) and the association with a seizure. Data presented as the odds ratio ± 95% CI. Any CI that does not cross one indicates a significant relationship between a pattern of acute nonadherence and seizure incidence as determined by Chi-Square analysis. C Odds ratios computed for the relationship between scenarios of acute nonadherence (y-axis) and the occurrence of a seizure. Data presented as the odds ratio ± 95% CI. Any CI that does not cross one indicates a significant relationship between a pattern of acute nonadherence and seizure incidence as determined by Chi-Square analysis