Spotlight on perampanel in the management of seizures: design, development and an update on place in therapy

Abstract

PurposePerampanel is a first-in-class antiepileptic medication approved for the treatment of partial (focal) seizures, and as adjunctive treatment for primarily generalized tonic–clonic seizures. The pharmacology, efficacy data, adverse-effect profile, pharmacokinetics and place in therapy are reviewed.SummaryPerampanel is indicated for use in patients with epilepsy who are 12 years of age or older. It is the first medication designed specifically to be a non-competitive antagonist at post-synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors. Efficacy in refractory seizures has been established, and ongoing efficacy demonstrated by post-marketing data. The drug is completely absorbed, and exhibits a half-life that allows for once-daily administration in doses up to 12 mg/day. Drug interactions are minimal, but increased doses may be necessary when given with strong inducers of cytochrome P450 enzymes, including when perampanel is co-administered with other antiepileptics that exhibit this property. The most common adverse effects noted in both clinical trials and post-marketing are dizziness and somnolence. Psychiatric and behavioral adverse events have been documented in both adult and pediatric patients, including those with no corresponding diagnostic history.ConclusionPerampanel is a novel adjunctive antiepileptic medication that is an effective option for adolescents and adults with partial seizures, and primarily generalized tonic–clonic seizures uncontrolled with other medications.

Plasma concentration and clinical effects of perampanel—The Kork experience

“…Plasma samples were drawn between 7.30 and 7.45 o'clock the next morning under fasting conditions. Because of the long half-life of approximately 105 h without the influence of enzyme-inducing drugs that reduce the elimination half-life markedly, [3,5,[7][8][9][10][11][12][13] PER plasma concentrations were measured only if the PER dose had been stable for at least 3 weeks. A stable plasma steady state is reached within 10-19 days after increases or decreases of the PER dose [7].…”

“…PER is the first in-class, selective, noncompetitive alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionate acid (AMPA) receptor antagonist used in epilepsy therapy [3][4][5] that was introduced to the German market in 2012 [2]. Because of its pharmacokinetic profile with an elimination half-life of up to 105 h, once daily dosing at bedtime is recommended [3][4][5][6][7][8][9][10][11][12].…”

“…PER is the first in-class, selective, noncompetitive alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionate acid (AMPA) receptor antagonist used in epilepsy therapy [3][4][5] that was introduced to the German market in 2012 [2]. Because of its pharmacokinetic profile with an elimination half-life of up to 105 h, once daily dosing at bedtime is recommended [3][4][5][6][7][8][9][10][11][12]. Potent cytochrome (CYP)3A4 inducers, such as carbamazepine, phenytoin, or oxcarbazepine, may markedly accelerate the elimination half-life time to approximately 25 h and decrease plasma concentrations of PER [3,5,[7][8][9][10][11][12][13].…”

“…Because of its pharmacokinetic profile with an elimination half-life of up to 105 h, once daily dosing at bedtime is recommended [3][4][5][6][7][8][9][10][11][12]. Potent cytochrome (CYP)3A4 inducers, such as carbamazepine, phenytoin, or oxcarbazepine, may markedly accelerate the elimination half-life time to approximately 25 h and decrease plasma concentrations of PER [3,5,[7][8][9][10][11][12][13]. This resulted in less efficacy in the pivotal phase III trials as an adjunct, although still statistically significant superiority over placebo was apparent [14].…”

“…It has been argued that the higher percentage of enzyme-inducing AEDs may have had an impact on these findings [16]. Therefore it has been recommended to consider dose increments if the baseline medication consists of potent enzyme inducers [3,5,9]. Real-world experience, as shown in several studies, indicates that, at least in some instances, patients clearly benefitted from even low doses (i.e., 4 mg of PER irrespective of the underlying AED therapy [4,9].…”