Perampanel: Does it have broad‐spectrum potential?

Abstract

This article reviews the profile of perampanel, a novel noncompetitive α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist, and its role as a potential broad-spectrum antiepileptic drug in the treatment of epilepsy. For this narrative review, data were collected using specified search criteria. Articles reporting the evidence for perampanel's efficacy from preclinical models, phase 3 clinical studies, observational studies, and descriptive evidence were included. AMPA receptors play a key role in mediating the action of glutamate at the excitatory synapse. Preclinical research showed the AMPA receptor blockade to constitute a promising target for antiepileptic drug therapy. In animal models, perampanel proved to be protective against seizures and reduce seizure severity and duration. Four phase-3 randomized controlled trials (3 in patients with focal seizures and one in primary generalized tonic-clonic seizures in idiopathic generalized epilepsy) have been completed. In focal (partial) onset seizures, perampanel (4, 8, and 12 mg) significantly reduced seizure frequency per 28 days (23.3%-28.8% vs 12.8%; P < .01) and responder rates (≥50% reduction in seizures) (28.5%-35.3% vs 19.3%; P < .05) compared with placebo. In primary generalized tonic-clonic seizures, perampanel 8 mg resulted in greater reduction in seizure frequency per 28 days (-76.5% vs -38.4%; P < .0001) and responder rate (64.2% vs 39.5%; P = .0019) than placebo. The efficacy, safety, and tolerability of perampanel have been reproduced in real-world clinical practice, and the agent has been shown to be effective in other epilepsy syndromes. Perampanel is a potentially broad-spectrum antiepileptic drug with a novel mechanism of action that may be a useful addition for patients with epilepsy with various seizure types. The availability of novel antiepileptic drugs for epilepsy treatment enables more individualized treatment for these patients.

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations

“…Perampanel is a new-generation and widely prescribed anticonvulsant and is well known for its non-competitive antagonist action at AMPA receptors (Hanada et al, 2011;Potschka & Trinka, 2019 AMPA antagonist 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3, 4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI-53655), which shares the binding site of perampanel (Hanada et al, 2011), was found to be superior to that of the competitive AMPA antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) in experimental seizure models (Yamaguchi, Donevan, & Rogawski, 1993). On the other hand, the binding affinity of perampanel could be much lower than that of CNQX (Chen et al, 2014;Honoré, Drejer, Nielsen, & Nielsen, 1989;Johansen et al, 1993).…”

The Novel Direct Modulatory Effects of Perampanel, an Antagonist of AMPA Receptors, on Voltage-Gated Sodium and M-type Potassium Currents

“…PER has been demonstrated to reduce neuronal excitation primarily through the blockade of AMPA receptors [1,2,3]. As a once-daily oral AED, it has been approved globally for the adjunctive treatment of partial epilepsy and primary generalized tonic-clonic seizures [4,5,6], although the underlying mechanism of actions through which PER exerts its broad-spectrum antiepileptic effect has not been fully elucidated.…”

The Effectiveness of Perampanel for Myoclonic Seizures in Down Syndrome with Isodicentric Chromosome 21

“…A low dose of perampanel was remarkably effective for myoclonic seizures in our patient. Perampanel, a third-generation anti-epileptic drug, is a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that is highly effective as an adjuvant therapy in patients with generalized and focal epilepsy [ 7 ]. Furthermore, perampanel was newly approved as monotherapy for focal epilepsy in Japan in January 2020 [ 8 ].…”