Introduction: Perampanel—New mode of action and new option for patients with epilepsy

Authors


Summary

With perampanel the first-in-class selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolprepionic acid (AMPA) receptor antagonist has been finally approved for add-on treatment in patients with focal-onset seizures. This suggests additional therapeutic potential in hitherto difficult-to-treat epilepsies.

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Prof. Dr. Bernhard J. Steinhoff is the Medical Director of the Kork Epilepsy Center at Kehl-Kork, Germany.

During the past two decades antiepileptic drug (AED) treatment options have been broadened by a variety of new AEDs. Whereas in other indications such as migraine or Parkinson's disease, new drug options have consisted of molecules with a new but common mechanism of action,[1] the group of new AEDs is primarily defined by the year of introduction and the proof of efficacy in randomized controlled trials. Therefore this group comprises a broad variety of differing compounds and modes of action.

It is tempting to speculate that patients with hitherto difficult-to-treat epilepsy might benefit from treatment with a new AED that offers a new anticonvulsant mode of action. Whereas some of the new compounds such as lamotrigine, oxcarbazepine, or eslicarbazepine acetate have addressed well-established modes of action, namely the blockage of use- and voltage-dependent sodium channels and others such as topiramate, felbamate, or zonisamide offered various mechanisms of action, only few of the new AEDs also led to the introduction of new modes of action:[1] Vigabatrin acts via the irreversible blockade of γ-aminobutyric acid (GABA) aminotransferase. The other selective GABAergic new AED, tiagabine, blocks the reuptake of GABA in the synaptic cleft. Gabapentin and pregabalin modulate calcium channels by specific receptor site binding. Levetiracetam acts via the binding to the presynaptic SV2A receptor site. Finally both of the latest introductions of new AEDs prior to perampanel—lacosamide and retigabine/ezogabine—offer a new mode of action, the former with the slow inactivation of sodium channels and the latter with the opening of inhibitory potassium channels.

Of interest, the postsynaptic glutatamatergic excitatory neurotransmission that is thought to play a major role in the generation of epileptogenesis[2, 3] has been barely addressed by the available AEDs. Topiramate and felbamate are examples of such drugs that offer some antiglutamatergic efficacy as a minor part of their anticonvulsant efficacy.[1]

With perampanel (PER), the first-in-class selective noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist has been clinically tested and finally approved for add-on treatment in patients with focal seizures with and without secondary generalization. AMPA receptors are located mainly at the postsynaptic membrane of excitatory synapses in the brain. They have a glutamate binding site and mediate glutamate-related signals.[2, 3] It is suggested that in human hippocampal and neocortical tissue, hypersensitive AMPA receptors and an augmented number of glutamate binding sites occur.[4, 5] Therefore, therapeutic potential is expected if AMPA receptor antagonists are applied.[2, 3, 6]

This supplement issue addresses the need for new and better antiepileptic drugs and the prelaunch evidence from preclinical and clinical data for the promising potential of PER. In addition, first clinical experiences from the Kork Epilepsy Center are included.

Conflict of Interest

Bernhard J. Steinhoff has received honoraria from Eisai, the manufacturer of Fycompa, for lectures and as an advisory board member. He confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this report is consistent with those guidelines.

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