Perampanel, a first-in-class, noncompetitive, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist recently approved for the adjunctive treatment of partial seizures in patients 12 years of age and older when other antiepileptic medications have failed.
{autotoc}Indications
In the EU and US, perampanel is approved in patients with epilepsy aged ≥12 years for the adjunctive treatment of primary generalized tonic-clonic seizures (GTCS) and partial-onset seizures (POS; with or without secondary generalization).It received approval for marketing from the European Commission in July, 2012. FDA approval was granted in October 2012.
Mechanism of action
The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor is type of glutamate receptor. The AMPA receptor is a ligand-gated cation channel. On binding to the ligand the cation channels open and the current speed through these channels is proportional to the number of sites on the receptor that remain occupied. The channels open and close very fast and the AMPA receptors are hence believed to mediate majority of the excitatory neurotransmission in the CNS. Increased glutamate binding results in increased intracellular calcium concentrations resulting in excitotoxicity.
Perampanel selectively binds to AMPA glutamate receptors and acts as a noncompetitive antagonist unable to be displaced by glutamate, even at excessive concentrations.The drug was deliberately engineered to affect known mechanisms of seizure initiation and proliferation.In the presence of perampanel, glutamate is still capable of binding to the AMPA receptor, but the anticipated response is inhibited by the presence of the drug at a separate binding site. It is believed that via this inhibition of glutamate receptor stimulation, seizure activity is suppressed.
Clinical trials
The drug has demonstrated efficacy in several clinical trials, and appears to exert its anti-seizure activity in a dose-dependent manner. The drug has a half-life of approximately 105 hours suggesting the medication might be a logical option for individuals who have difficulty with adherence to medications that require multiple daily doses. Once-daily dosing is possible because of the extended half-life of perampanel (52–129 hours after a single dose).
The data from Phase III trials showed a consistent decrease in median seizure frequency. carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, and valproic acid were the other medications concomitantly used by the trial participants. Perampanel and levetiracetam co-administration resulted in a change of −39%, while use with carbamazepine produced a change of −18%. However no particular combination therapy has been identified to date as being beneficial, since the correlation between drug response and plasma concentration is maintained irrespective of the adjuvant medication used.
Pharmacokinetics and metabolism
Perampanel displays a linear, one-compartment pharmacokinetic profile with first-order elimination. It is approximately 95% bound to plasma proteins. Following intake maximal serum concentrations are rapidly attained . The absorption is not affected by food although when taken after meals it may take one to three hours to reach maximal levels.
Perampanel undergoes extensive metabolism primarily by the cytochrome P-450 enzymes 3A4 and 3A5 followed by glucuronidation. In the presence of mild to moderate liver dysfunction (Child–Pugh scores A or B) the clearance of perampanel decreases by approximately 50% and hence dose adjustments are necessary. It should be avoided in the presence of severe liver disease.
There is currently insufficient data regarding its pharmacokinetics in the presence of renal dysfunction and in haemodialysis.
Drug interactions
Medications that induce cytochrome P-450 enzymes have been shown to affect perampanel plasma concentrations.
Concomitant therapy with enzyme-inducing antiepileptics (carbamazepine, oxcarbazepine and phenytoin) have been shown to decrease Perampanel levels by as much as 67% . Hence, initial dosing at double the normal starting dose is recommended in the presence of these medications.
Phenobarbital does not alter plasma concentrations of perampanel (though drug labeling suggests it is possible), and no other clinically significant interactions with other antiepileptic agents have been identified to date. The manufacturer however recommends increasing the doses when used along with hepatic enzyme inducing medications and neutraceuticals for e.g. St. John's Wort or Rifampicin.
Inhibitors of cytochrome P-450 enzyme metabolism may increase the likelihood of experiencing adverse events related to the use of perampanel because of higher than normal plasma concentrations, although so far no medication has been shown to increase concentrations of perampanel to this extent.
The antifungal agent ketoconazole increases perampanel concentrations by approximately 20%.
Perampanel may decrease the levels of other medications, including levonorgestrel contraceptives, the levels of which have been shown to be decreased by 40% following high-dose (12 mg/day) perampanel administration. Specific dosing recommendation are not available in such situations and alternate back up contraceptive measures are recommended.
Dosage
The starting dose (in the absence of enzyme inducers) is 2 mg, and the drug may be titrated in 2 mg increments each week to a target of 8–12 mg per day. Dosing should be individualized based on concomitant therapy, specifically the presence of co-administered enzyme-inducing antiepileptic agents, which requires the initial dose to be doubled to 4 mg daily at therapy outset.
Safety and tolerability
The drug is well tolerated overall, with most reported adverse events described as mild or moderate in nature
Adverse effects
Treatment-emergent adverse events are most commonly CNS-related (e.g. dizziness, somnolence, fatigue and irritability) and dose-related; however, most were of mild to moderate intensity. The FDA approved package insert for the drug contains a boxed warning describing aggression, hostility, irritability, anger, and homicidal ideation and threats as adverse reactions associated with perampanel use that warrant increased vigilance.
Further reading:
Faulkner, M. (2014). Perampanel for the Control of Drug-Resistant Partial-Onset Seizures in Patients 12 years and Older. Clinical Medicine Insights: Therapeutics, 33. doi:10.4137/CMT.S11674
Frampton, J. E. (2015). Perampanel: A Review in Drug-Resistant Epilepsy. Drugs. doi:10.1007/s40265-015-0465-z
Eisai. (n.d.). Fycompa® (Perampanel): Mode Of Action. Retrieved September 21, 2015, from http://www.fycompa.eu/mode-of-action.php
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