PeraMpanel

Absorption

After oral adminitration, perampanel is absorbed rapidly and completely.

Toxicity

The FDA label includes an important warning of serious or life-threatening behavioral and psychiatric adverse reactions including aggression, hostility, irritability, anger, and homicidal thoughts in patients taking perampanel.

Description

In October 2012, the US FDA approved perampanel for the treatment of partial onset seizures in epileptic patients who are at least 12 years old. Perampanel is the first AMPA receptor antagonist to receive FDA approval as an AED. AMPA glutamate receptors are found primarily on postsynaptic neurons in the brain. As a selective, noncompetitive antagonist of AMPA, parampanel prevents ion channel opening and reduces propagation of action potential. Parampanel was discovered through lead optimization of a commercially available compound, 2,4-diphenyl-4H-[1,3,4]oxadiazin-5-one, which was identified by high-throughput screening of a compound collection employing a rat cortical neuron AMPA-induced cell-death assay. Modifications of aromatic rings at positions 1, 3, and 5 while changing the core to pyridone led to parampanel which inhibited AMPA-induced calcium influx (IC₅₀=60 nM). Parampanel had a minimum effective oral dose of 2 mg/kg in an AMPA-induced mouse seizure model. The synthesis of parampanel was accomplished via a 6-step route utilizing Suzuki–Miyaura couplings and modified Ullmann reactions for incorporation of aryl groups.

Originator

Eisai (Japan)

The Uses of PeraMpanel

Isotope labelled Perampanel (P285520), is an antiepileptic drug. It inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-induced increases in intracellular Ca2+ and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation.

Background

Perampanel is a noncompetitive AMPA glutamate receptor antagonist. It is marketed under the name Fycompa? and is indicated as an adjunct in patients over 12 years old for the treatment of partial-onset seizures that may or may not occur with generalized seizures. The FDA label includes an important black-boxed warning of serious or life-threatening behavioral and psychiatric reactions in patients taking Fycompa?.

Indications

Perampanel is indicated for the treatment of partial-onset seizures with or without secondarily generalized seizures in epileptic patients four years of age and older. It is also indicated as an adjunct in the treatment of primary generalized tonic-clonic seizures in epileptic patients aged 12 years and older.

Definition

ChEBI: A member of the class of bipyridines that is 2,3'-bipyridin-6'-one substituted at positions 1' and 5' by phenyl and 2-cyanophenyl groups respectively. Used as an adjunctive therapy for the treatment of partial-onset seizures in patients with epilepsy.

brand name

Fycompa

Pharmacokinetics

Perampanel is involved in inhibiting neuronal excitation in the central nervous system leading to such effects as decreased pyschomotor performance.

Clinical Use

Selective AMPA-type glutamate receptor antagonist:
Antiepileptic

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: anticonvulsant effect antagonised; avoid with St John’s wort.
Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, oxcarbazepine and phenytoin.
Antimalarials: anticonvulsant effect antagonised by mefloquine.
Antipsychotics: anticonvulsant effect antagonised.
Orlistat: possibly increased risk of convulsions.
Progestogens: high-dose perampanel reduces plasma concentration of progestogens (possibly reduced contraceptive effect).

Metabolism

Perampanel is highly metabolized by CYP3A4 and/or CYP3A5 primary oxidation and by sequential glucuronidation.

Metabolism

Extensively metabolised via primary oxidation via the cytochrome P450 isoenzyme CYP3A sub family and sequential glucuronidation.
Perampanel is excreted in the urine and faeces mainly as oxidative and conjugated metabolites.