Perampanel: New drug for treatment of refractory partial onset seizures

Santosh Kumar Singh; Dick B. S. Brashier

doi:10.4103/0975-9727.135796

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Year : 2014 | Volume : 5 | Issue : 2 | Page : 195-199

Perampanel: New drug for treatment of refractory partial onset seizures

Santosh Kumar Singh, Dick B. S. Brashier
Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication

1-Jul-2014

Correspondence Address:
Santosh Kumar Singh
Department of Pharmacology, Armed Forces Medical College, Sholapur Road, Pune - 411 040, Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0975-9727.135796

Abstract

Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile hydrate) is the latest antiepileptic drugs for treatment of refractory partial onset seizures. Perampanel inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-induced increase in intracellular Ca ²⁺ and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation. Three Phase III multicenter, randomized, double-blind, placebo-controlled trials demonstrated the efficacy and good tolerability of perampanel as adjunctive treatment in patients with refractory partial-onset seizures. The drug is approved for use in the European Union and United States. The pharmacology of perampanel offers potential as more than just another new antiepileptic drug. This first-in-class drug will provide another option for practitioners of rational polytherapy.

Keywords: AMPA, antiepileptics, perampanel, refractory partial onset seizures

How to cite this article:
Singh SK, Brashier DB. Perampanel: New drug for treatment of refractory partial onset seizures. Muller J Med Sci Res 2014;5:195-9

How to cite this URL:
Singh SK, Brashier DB. Perampanel: New drug for treatment of refractory partial onset seizures. Muller J Med Sci Res [serial online] 2014 [cited 2023 May 30];5:195-9. Available from: https://www.mjmsr.net/text.asp?2014/5/2/195/135796

Introduction

Epilepsy encompasses a diverse group of seizure disorders which is caused by a variety of cellular and molecular alterations in the brain which primarily affect the cerebral cortex, leading to recurrent unprovoked epileptic seizures. ^[1] Epileptic seizure is defined as a transient occurrence of signs/symptoms due to abnormal excessive or synchronous neuronal activity of the brain. ^[2] However, despite the newer agents with novel mechanisms of action, more than one third of patients continue to experience partial seizures. ^[3] Currently, AED combinations are chosen based on avoidance of drug-drug interactions and unwanted side effects rather than on evidence of improved efficacy. ^[4] However, efficacy of the newer drugs, as defined by seizure control, was not demonstrably different from drugs available before 1980. ^[5] AMPA receptors, named after the selective agonist a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), are activated by glutamate, the major excitatory neurotransmitter, which is thought to play a key role in inducing seizures by initiating and synchronizing glutamatergic transmission. ^[6] Glutamate acts on both ionotropic and metabotropic glutamate receptors. Binding of glutamate to AMPA, opens AMPA receptors, which allows cations, mainly sodium, to enter into the cell. This results in a brief depolarization of the postsynaptic membrane. Summation of excitatory postsynaptic potentials leads to the firing of action potentials by the postsynaptic neuron. ^[7] In animal models of epilepsy, it is seen that activation of both NMDA and AMPA receptors play an important role in seizure generation. However, in other models, antagonists of AMPA receptors alone nearly suppressed all discharges. ^[8] Furthermore, NMDA antagonists might paradoxically enhance the frequency of bursting at the same time that they reduce the burst duration and the number of spikes in each discharge. ^[9] Finally, epileptic discharges observed in human neocortical tissue removed during epilepsy surgery were found to be more sensitive to AMPA than to NMDA-receptor blockers. ^[10] Two selective AMPA antagonists, talampanel and perampanel, have been evaluated in humans. Although talampanel has been positively evaluated in a Phase II trial as an add-on therapy in drug-resistant partial epilepsy, its relatively short half-life has limited its clinical development. ^[11] In contrast, perampanel (PER) has recently been approved in the US and Europe as an add-on treatment for drug-resistant partial epilepsy.

Perampanel is a structurally distinct non-competitive AMPA receptor antagonist which inhibits AMPA-induced increase in intracellular Ca ²⁺ and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation. In July 2012, perampanel was granted market authorization by the European Commission as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy who are aged 12 years and older. ^[12] The US Food and Drug Administration (FDA) granted approval for perampanel in October 2012. Structure of perampanel is depicted in [Figure 1] and mechanism of action of perampanel and other antiepileptic drugs are depicted in [Figure 2]. ^[13]

Figure 1: Chemical structure of perampanel (2-[2-oxo-1-phenyl-5-pyridin- 2-yl-1,2-dihy dropyridin-3-yl] benzonitrile hydrate)

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Figure 2: Mechanisms of action of antiepileptic drugs. Perampanel display a spectrum of mechanisms of action, with effects on both inhibitory (left-hand side) and excitatory (right-hand side) nerve terminals. AMPA, α-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid; GABA, γ-aminobutyric acid; GAT-1, sodium- and chloride-depended GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A

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Mode of Action

Perampanel inhibits AMPA-induced increase in intracellular Ca ²⁺ and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation. Phases I and II clinical studies revealed a favorable safety and tolerability profile that furthered the proof of concept for the safety, efficacy, and tolerability of perampanel that was observed in three Phase III clinical trials in Europe, North America, and Australia. ^{[14],[15],[16]} Perampanel demonstrated a broad spectrum of activity in rodent and other preclinical seizure models. ^[6] The precise mechanism of action has not been fully determined. Perampanel reduces calcium influx mediated by AMPA receptors in cultured cortical neurons. In vitro studies revealed its mechanism of action as a selective noncompetitive AMPA-receptor antagonist that impacts neurotransmission by high potency reduction of neuronal excitability in the brain. ^[17] Perampanel also acts at the N-methyl-D-aspartate (NMDA) and the kainate receptors in the excitatory postsynaptic membranes of the neurons, though the principal ionotropic glutamatergic receptor activity involves AMPA. ^[6],[18] In mouse models, perampanel showed a protective effect against audiogenic, pentylenetetrazole, and maximal electroshock-induced seizures studied in monotherapy and in combination with other AEDs. ^[6] In amygdala-kindled rats, perampanel significantly increased after discharge threshold and significantly reduced motor seizure duration, after discharge duration, and seizure severity recorded at 50% higher intensity than after discharge threshold current. Based upon its mechanism of action, perampanel has been studied in other degenerative neurological disorders where excessive glutamatergic activity has been implicated in the primary disease process. ^[19]

Clinical Pharmacokinetics and Interactions

Following oral administration, perampanel is rapidly and almost completely absorbed, with peak plasma concentrations reaching at 15 minutes to 2 hours after oral dosing. Bioavailability approaches 100% and the protein binding is 95%. There is a negligible first-pass metabolism, and it is slowly eliminated with a steady-state plasma concentration apparent after 2 weeks. The elimination half-life is long, estimated around 70 hours, allowing a once-daily regimen. ^[18],[20] It is primarily eliminated by hepatic oxidative metabolism via oxidation and sequential glucuronidation. Perampanel is 95% bound to plasma proteins and is extensively metabolized. About 70% of the dose is excreted in the feces whereas less than 2% is excreted unchanged in the urine. It is primarily metabolized by CYP3A4 of the P450 enzyme system, though other CYP enzymes may also be involved. ^[21] It does not function as an enzyme inducer or inhibitor. Enzyme-inducing AEDs including carbamazepine, oxcarbazepine, and phenytoin increased the clearance of perampanel and decreased its plasma concentration by at least half. Topiramate reduced the AUC of perampanel by 20%, while lamotrigine, levetiracetam, valproate, zonisamide, and benzodiazepines had no effect on perampanel clearance. Perampanel reduced the clearance of oxcarbazepine by 26% and reduced the clearance of carbamazepine, valproate, and lamotrigine by, 10%, though the impact on efficacy is expected to be clinically insignificant. ^[22] A prospective study evaluated the modifications of PER pharmacokinetics in subjects with hepatic impairment. In patients of hepatic impairment elimination half-life was increased by about 2-fold but there was no effect of age on the pharmacokinetics of PER so that no dose adjustment is needed for the elderly. ^[23] Perampanel is commercially available in round, biconvex, film-coated tablets. Tablet strengths include 2, 4, 6, 8, 10, and 12 mg formulations. Maximum frequency for dosage increases is every 2 weeks starting at 2 mg/day. There are no adequate and well-controlled studies in pregnant women, and perampanel is rated as Category C. Oral administration of perampanel to pregnant rats at any dose throughout organogenesis resulted in an increase in visceral abnormalities. ^[22] Food slows the rate of absorption but does not affect the extent of absorption. No significant effect of sex, race, or age in patients between 12-74 years was seen. Patients older than 12 years of age may be dosed as adults. In dose-ranging studies, 2-12 mg of active drug per day were evaluated. A minimal effective dose of 4 mg and a plateau in efficacy was observed at 8 mg daily during Phase III clinical trials. High doses of perampanel produced euphoria that was similar to ketamine 100 mg and alprazolam 3 mg. ^{[14],[15],[16]}

Efficacy

Two Phase II randomized, double-blind, placebo-controlled dose-escalation studies 206 and 208 of 201 patients used pharmacokinetic and pharmacodynamics analyses to predict the range of effective doses for the Phase III studies. The minimum effective dose was 4 mg/day, mid effective dose was 8 mg/day, and high effective dose was 12 mg/day. Although the studies did provide data on preliminary efficacy, they were not powered to provide conclusive data on efficacy. ^[24] An open-label extension study followed up on 138 patients in studies for up to 4 years. The average duration of exposure to perampanel was 2.2 years at doses of 2-12 mg/day. The median (range) percent change in seizure frequency per 28 days relative to baseline was −31.5% (−99.2% to 512.2%). ^[24] The responder rate, defined as the proportion of patients experiencing a 50% reduction in seizure frequency, for all 138 patients was 37.0%. ^[25] Three Phase III multicenter, randomized, double-blind, placebo-controlled trials (studies 304, 305, and 306) evaluated the efficacy of adjunctive perampanel for refractory partial-onset seizures in patients age 12 years on one to three concomitant antiepileptic drugs (AEDs). All three trials were of similar design. ^{[14],[15],[16]} In study 306, 706 patients were taken and minimally effective dose was noted. The 2 mg/day dose was not statistically different than placebo. The median percent change in seizure frequency was −23.3% (P = 0.0026) and −30.8% (P = 0.0001) and responder rates were 28.5% (P = 0.0132) and 34.9% (P = 0.0003) for doses of 4 mg/day and 8 mg/day, respectively. ^[14] Studies 304 and 305 used higher doses of perampanel. Study 304 enrolled 388 patients from North, Central, and South America and used once-daily dosing of perampanel at 8 mg and 12 mg/day. Median percent change in seizure frequency was −26.3% (P = 0.0261) and −34.5% (P = 0.0158) for doses of 8 mg and 12 mg/day, respectively. However, the responder rates for 8 mg and 12 mg/day were 37.6% (P = 0.0760) and 36.1% (P = 0.0914), respectively, and not statistically different than placebo. ^[15] Study 305 consisted of 386 patients from Europe, North America, and Australia. The median percent change in seizure frequency from baseline per 28 days was -30.5% (P = 0.001) and −17.6% (P = 0.011) and responder rates were 33.3% (P = 0.002) and 33.9% (P = 0.001) for doses of 8 mg/day and 12 mg/day, respectively. During the maintenance period, 2.8% of patients in the 8-mg group and 6.5% of the patients in the 12-mg group became seizure free, compared to 1.7% in the placebo group. During the maintenance period, 2.8% of patients in the 8-mg group and 6.5% of the patients in the 12-mg group became seizure free, compared to 1.7% in the placebo group. ^[16] Therefore, results from 304 and 305 indicate that there was not a greater benefit for the 12 mg/day dose versus the 8 mg/day dose, but that doses up to 12 mg/day may provide additional benefit in efficacy for some patients, although the numbers were too small to provide any definite conclusions. ^[22] Finally, an extension study of all three Phase III trials, which included 1218 patients, demonstrated that the reduction in seizure frequency in patients on adjunctive once-daily perampanel average dose of 10 mg/day was maintained during the 1- to 2-year monitoring period. The overall median percent change in seizure frequency was −46.5% (weeks 40-52, n = 731) and −58.1% (weeks 92-104, n = 59), and responder rates were 46.9% and 62.7%, respectively. The rate of seizure freedom was 7.1% in patients with 12 months of data. ^[26]

Safety/Tolerability

Treatment with adjunctive perampanel is safe, and tolerability is acceptable. Doses of 4-12 mg/day were well tolerated both once and twice daily in two Phase II dose-escalation studies, and the most common side effects reported in study 208 were dizziness (57.9%), somnolence (31.6%), and headache (18.4%). Fatigue, diarrhea, and rhinitis were all reported in 10.5% of patients. No serious adverse effects or deaths were reported. ^[24] Of the three Phase III studies, the most common adverse effects with the 8 mg/day dose were dizziness (26.6%-37.6%), somnolence (12.4%-18.0%), headache (8.5%-15.0%), and fatigue (5.3%-13.2%). ^{[14],[15],[16]} No evidence of an adverse effect of PER either on the hepatobiliary function, the renal function or shown by electrocardiography emerged. No death occurred during Phase II and Phase III studies. One death, related to possible Sudden Unexplained Death in Epilepsy (SUDEP), occurred in the extension phase of Phase II studies. ^[26] In a recent meta-analysis comparing some of the newer AEDs including perampanel, the odds ratio for withdrawal rate of perampanel was 0.50, which indicates better tolerability of perampanel compared to all the other newer AEDs except brivaracetam. ^[27]

Patient-Perspectives

Perampanel is a new type of AED with an encouraging clinical profile based upon a design that inhibits excitatory amino acids that are linked to epileptic seizure generation and spread. ^[28] Unique theoretical concerns for perampanel include behavioral and psychiatric side effects because of the drug's mechanism of action (similar to phencyclidine). The use of perampanel should be monitored to assess patients for temporal signs of anger; aggression; unfavorable changes in mood, personality or behavior; and other behavioral symptoms, including the emergence of suicidal thoughts or gestures. Perampanel should be reduced if this occurs; if symptoms are severe or worsening, then it should be discontinued immediately. Withdrawing the drug seems to produce no unexpected withdrawal-like symptoms, though abrupt discontinuation may increase seizure frequency. Patients should be advised not to drive or operate machinery until sufficient experience on perampanel has been attained, especially if is co administered with other central nervous system (CNS) depressant medications, including alcohol. In the absence of co administered enzyme-inducing antiepileptic drugs, the initial starting dose is 2 mg orally at bedtime (4 mg with enzyme-inducing antiepileptic drugs). This may be increased by 2 mg/day every week to a total of 4 to 8 mg/day. The maximum recommended daily dose is 12 mg at bedtime. Laboratory testing, changes in vital signs, and altered cardiac function noted on EKG parameters have not been observed; therefore, seizure control is indicative of efficacy and routine serologic monitoring is not required. The FDA has recommended that perampanel be classified as a scheduled drug with a potential for abuse or addiction. Side effects include irritability, aggression, anger, anxiety, paranoia, euphoric mood, and agitation. Serious or life-threatening psychiatric and behavioral adverse reactions have been reported in patients taking perampanel. ^[22]

Conclusion

Perampanel is the first AMPA-receptor antagonist marketed for the treatment of partial onset seizures with or without secondary generalization. Its efficacy in clinical trials is similar to that of AEDs approved for use in the past decade. The proportion of patients rendered seizure-free in the clinical trials was about 7%, which is also in line with data from drug trials of other AEDs. Thus, perampanel does not appear to confer significantly better seizure control than other AEDs available in the US and EU. Perampanel is considered a safe drug with an acceptable tolerability profile. The most common side effects are well-known to physicians using AEDs, and include the usual suspects such as dizziness, somnolence, headache, and fatigue. Anxiety and irritability may be seen in some patients taking perampanel, but there was no evidence of increased risk for suicidality, psychosis, or major depression. With this efficacy and side-effect profile, perampanel promises to be a useful drug for treating epilepsy patients.

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