PeraMpanel Chemical Properties

Boiling point:

619.1±55.0 °C(Predicted)

Density 

1.31±0.1 g/cm3(Predicted)

solubility 

Soluble in DMSO

form 

Powder

pka

4.73±0.19(Predicted)

PeraMpanel Usage And Synthesis

Description

Perampanel (licensed in 2012) is a third- generation AED known with the proprietary brand name of Fycompa® (Eisai, Hatfield) in the UK and Banzel® (Eisai, Hatfield) in the USA.

Indications

Epilepsy: Adjunctive treatment of focal seizures with or without secondary generalization and primary generalized tonic- clonic seizures.

Dose titration

Epilepsy— adjunctive therapy: 2 mg nocte for at least 14 days, then increased by 2 mg every 14 or more days; usual maintenance 4– 8 mg nocte (max. 12 mg nocte).

Interactions

With AEDs

• Some AEDs known as CYP450 3A enzyme inducers (carbamazepine, oxcarbazepine, phenytoin) have been shown to increase perampanel clearance and consequently to decrease plasma concentrations of perampanel. Carbamazepine, a known potent enzyme inducer, reduced perampanel levels by two- thirds in a study performed on healthy subjects
• In the epilepsy population pharmacokinetic analysis, perampanel was found to decrease the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolized by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is not known.

With other drugs

• Strong inducers of cytochrome P450, such as rifampicin and St John’s Wort (Hypericum perforatum), are expected to decrease perampanel concentrations.
• In healthy subjects, the CYP3A4 inhibitor ketoconazole increases perampanel exposure.
• Perampanel can make certain hormonal contraceptives such as levonorgestrel less effective.
• Decrease in exposure of midazolam may be caused by perampanel.

With alcohol/food

• Drinking alcohol while taking perampanel can affect a patients’ alertness and ability to drive or use tools or machines. It can also aggravate irritability, confusion, and depression.
• There are no specific foods that must be excluded from diet when taking perampanel.

Special populations

Hepatic impairment

• Increase at intervals of at least 2 weeks, up to a maximum of 8 mg daily, in mild- to- moderate impairment.
• Avoid in severe impairment.

Renal impairment
Avoid in moderate or severe impairment.

Pregnancy

• There are limited amount of data available on the use of perampanel in pregnant women and the potential risk for humans is unknown.
• Perampanel is not recommended in pregnancy and female patients must use a reliable method of contraception to avoid becoming pregnant while being treated with perampanel (this should be continued for 1 month after stopping treatment).
• As perampanel can make certain hormonal contraceptives such as levonorgestrel less effective, other forms of safe and effective contraception (such as a condom or coil) should be used when taking perampanel (this should be continued for 1 month after stopping treatment).
• Perampanel has been found to be present in milk in animal studies and it is recommended that breastfeeding should be avoided.

Behavioural and cognitive effects in patients with epilepsy

For this third- generation agent, clinical experience is still limited, and little is known about its positive and negative psychotropic properties, and their implications for the management of behavioural symptoms in patients with epilepsy. There are initial reports of behavioural disturbances (especially depression, anxiety, irritability, and psychosis), which seem to be dose- related and tend to appear within the first weeks of treatment. Reports of cognitive effects (mainly affecting memory) are relatively rare.

Psychiatric use

Perampanel has no indications for the treatment of psychiatric disorders. There is insufficient experience with perampanel to draw any conclusion regarding its psychotropic profile.

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)

Uses

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.

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

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

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.

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