Perampanel

Perampanel (Fycompa) AM PA Receptor Antagonist for the Treatment of Seizure... 

Perampanel (1) represents a new class of noncompetitive AMPA receptor antagonists used for the treatment of partial-onset seizures in epileptic patients 12 and older. It is approved for marketing by the European Medicine Agency (EMA, 2011) and the Food and Drug Adminisbation (EDA, October 2012). This chapter describes in detail the pharmacological profile and chemical synthesis of perampanel. 

In humans, perampanel is rapidly and nearly completely absorbed achieving its Cmax in about 1 h. ° The compound readily crosses the BBS and is not a P-glycoprotein substrate or a substrate of any other known membrane transporter such as breast cancer resistance protein (BCRP). Perampanel has a plasma half-Ufe in humans of 53-163 h, although this can be reduced to 25 h in patients dosed with carbamazepine, a CYP3A4 inducer. Elimination is primarily fecal (70%), but it is also eliminated via the urine (30%) as a mixture of oxidative and conjugated metabolites. ... 

Perampanel (1) is a potent selective noncompetitive AMPA receptor antagonist found to be effective for the treatment of refractory partial-onset seizures. It is dosed orally once a day, usually at night before sleep. The minimally effective dose is 4 mg with doses of 8 and 12 mg being the most effective. The drug was first approved for marketing under the brand name Fycompa by the EMA. Subsequently, perampanel was approved in the United States for the control of partial-onset seizures. 

Two phase 1 clinical studies were initiated to evaluate the initial safety and PK of single and multiple daily dosing of perampanel in healthy male subjects (18 5 years). Both studies were randomized, double-blind, and placebo-controUed. The drug was rapidly absorbed and slowly eliminated with steady state being achieved on Day 14 in the multiple-dose study. AEs were reported as mild to moderate, with dizziness, fatigue, and somnolence being most common. 

Phase 3 studies (EXPLORE) were conducted in a similar manner to phase 2 (randomized, double-blind, etc.) on about 1500 patients with refractory partial-onset seizures currently taking one or more AEDs (Table 3). The first two studies (304 and 305) were dose escalating and assessed the efficacy and tolerability of 8 and 12 mg doses of perampanel. The third study (306) assessed 2,4, and 8 mg doses. Analysis of the data from all three studies indicated that addition of perampanel at 4, 8 or 12 mg/day reduced median 28-day seizure frequency by 23-29% versus placebo (13%). The responder rate was also higher with perampanel (29-35%) versus placebo (19%). The 2 mg/day dose failed to show any statistically significant differences compared to placebo. 

Two open-label extension (OLE) studies have also been conducted.The first, involving 138 patients from the phase 2a study, found that after approximately 4 years, 38.4% of patients remained on perampanel and decreases in seizure frequency were maintained ( 31%) after a median duration of 116 weeks. The second study, comprising 1218 patients from the phase 3 studies, showed that decreases in seizure frequency were maintained. 

On an industrial scale (100+ kg), perampanel can be prepared in six linear steps in a 24% overall yield. Addition of bromine to a solution of 2-methoxypyridine 23 cleanly afforded 5-bromo-2-methoxypyridine 24 in 86% yield. The 5-pyridyl moiety was introduced via a metal-halogen exchange on bromide 24 followed by addition to 2-(phenylsulfonyl)pyridine versus the biaryl couplings found in earlier routes. Acid hydrolysis of 25 gave pyridinone 26, which underwent a copper-catalyzed V-aryl coupling to afford pyridinone 27 in 83% yield. NBS bromination smoothly provided the bromo pyridinone 28, which was coupled with boronate 29 to give perampanel (1). 

In summary, perampanel (1) is a selective noncompetitive AMPA receptor antagonist approved by FDA for the treatment of refractory partial-onset seizures in patients 12 years or older. It is currently prescribed as an add-on therapy for patients taking antiepileptic drugs but still experience seizures. Perampanel has proven to be safe and effective in reducing seizures, thereby giving physicians and patients a welcome addition to the current standard of care for this affliction. 

Placebo-controlled studies Several multicenter placebo-controlled studies were performed to assess the efficacy and safety of perampanel [115-117 ], [118 ]. Both 8 mg/day and 12 mg/day doses were evaluated. The most common adverse effects attributed to the medication were dizziness, somnolence, headache, fatigue, falls, irritability, ataxia, and weight gain. All the symptoms except weight increase and irritability were thought to be dose-dependent. 

Psychiatric In addition to the adverse effects listed above, as many as 15% of patients exposed to perampanel have been reported to experience psychiatric symptoms including aggressive behavior, insomnia, and irritability. Additionally, some concerns have been raised for the potential for abuse as it can produce euphoric symptoms at doses of 24-36 mg/day [119 ]. 

French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures randomized phase 111 study 304. Neurology August 7,2012 79(6) 589-96. 

French J A, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures results of randomized global phase HI study 305. Epilepsia January 2013 54(l) 117-25. 

Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase in study 306 adjunctive perampanel for refractory partial-onset seizures. Neurology May 1,2012 78(18) 1408-15. 

Franco V, Crema F, ludice A, Zaccara G, Grillo E. Novel treatment options for epilepsy focus on perampaneL Pharmacol Res April 2013 70(l) 35-40. 

Rheims S, R)fvlin P. Profile of perampanel and its potential in the treatment of partial onset seizures. Neuropsychiafr Dis Treat 2013 9 629-37. 

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