Perampanel is 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.

Indications

• Approved Use:
  • EU and US: For patients with epilepsy aged 12 years and older.
  • Adjunctive treatment for:
    • Primary generalized tonic-clonic seizures (GTCS)
    • Partial-onset seizures (POS), with or without secondary generalization.
• Approval Dates:
  • European Commission: July 2012
  • FDA: October 2012

Mechanism of Action

• AMPA Receptor:
  • Type of glutamate receptor and ligand-gated cation channel.
  • Mediates the majority of excitatory neurotransmission in the CNS.
  • Increased glutamate binding leads to increased intracellular calcium and excitotoxicity.
• Perampanel:
  • Selectively binds to AMPA receptors.
  • Acts as a noncompetitive antagonist, not displaced by glutamate.
  • Inhibits glutamate receptor stimulation, suppressing seizure activity.

Clinical Trials

• Efficacy:
  • Demonstrated in several clinical trials.
  • Anti-seizure activity is dose-dependent.
  • Half-life: Approximately 105 hours.
  • Suitable for once-daily dosing.
• Phase III Trials:
  • Consistent decrease in median seizure frequency.
  • Common concomitant medications: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, valproic acid.
  • Co-administration results:
    • With levetiracetam: -39%
    • With carbamazepine: -18%
  • No particular combination therapy identified as more beneficial.

Pharmacokinetics and Metabolism

• Pharmacokinetics:
  • Linear, one-compartment profile with first-order elimination.
  • ~95% plasma protein binding.
  • Rapid attainment of maximal serum concentrations.
  • Absorption unaffected by food.
• Metabolism:
  • Primarily by cytochrome P-450 enzymes (3A4 and 3A5), followed by glucuronidation.
  • Reduced clearance by ~50% in mild to moderate liver dysfunction.
  • Avoid in severe liver disease.
• Renal Dysfunction:
  • Insufficient data on pharmacokinetics in renal dysfunction and haemodialysis.

Drug Interactions

• Cytochrome P-450 Enzyme Inducers:
  • Decrease perampanel plasma concentrations.
  • Enzyme-inducing antiepileptics (carbamazepine, oxcarbazepine, phenytoin) decrease levels by up to 67%.
  • Initial dose recommendation: Double the normal starting dose.
• Other Medications:
  • Phenobarbital does not alter plasma concentrations significantly.
  • Hepatic enzyme inducers (e.g., St. John's Wort, Rifampicin) require dose adjustments.
  • Inhibitors of cytochrome P-450 may increase adverse event likelihood.
  • Ketoconazole increases concentrations by ~20%.
  • May decrease levels of other medications (e.g., levonorgestrel contraceptives by 40%).

Dosage

• Starting Dose:
  • 2 mg, titrated in 2 mg increments weekly.
  • Target: 8–12 mg per day.
  • Individualize based on concomitant therapy, especially enzyme-inducing antiepileptic agents (initial dose: 4 mg daily).

Safety and Tolerability

• General Tolerance:
  • Well tolerated with mild to moderate adverse events.
• Adverse Effects:
  • Commonly CNS-related (dizziness, somnolence, fatigue, irritability).
  • FDA boxed warning for aggression, hostility, irritability, anger, and homicidal ideation.

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