Efficacy and Safety of Perampanel in the Treatment of Refractory Status Epilepticus

ILAE (International league against epilepsy) defines status epilepticus (SE) as generalized tonic-clonic seizures > 5 minutes or focal impaired awareness seizure > 15 min or recurrent seizures with alteration of consciousness in between seizures.

Refractory status epilepticus (RSE) is defined as failure to respond to first line benzodiazepines and one antiepileptic drug (AED). It often requires treatment with anesthetic drugs and continuous EEG monitoring for diagnosis and titration of medications. Status epilepticus (SE) is estimated to be refractory in about 30 % of cases, associated with increased morbidity and mortality and requires continuous EEG monitoring to guide treatment [1]. It is seen across all ages, and around 200,000 cases are seen in the United States annually resulting in significant morbidity and mortality [2]. Morbidity and mortality of SE and especially RSE is due to prolonged stay in the ICU and at times treatment from IV anesthetics including hemodynamic instability, and related infections of the ICU stays.

Standard of Care treatment of SE and RSE

Rapid termination of the SE is the primary goals of SE treatment with evidence indicating that if left untreated, SE becomes harder to terminate [3,4]. In a patient with SE, the first AED should be started at the onset concomitantly with the first line benzodiazepine or soon after. The agents of choice are typically those available in IV (intravenous) formulation with purpose of fast and safe administration in a seizing patient. These include phenytoin (PHT)/fosphenytoin, valproic acid (VPA), levetiracetam (LEV); lacosamide (LCM) with no clear evidence that one drug is superior [5,6]. Beyond the introduction of a second seizure medication, there is no unified consensus or clear evidence to guide treatment at that stage of RSE.

Other AED are used as add-on therapy in the treatment of SE when benzodiazepine (1st agent) and IV AED (2nd agent) fail. These have been demonstrated to be efficacious in different cohorts and case series and include but not limited to clobazam, topiramate, oxcarbazepine and eslicarbazepine [7].

Perampanel

Perampanel (PMP) has recently been shown to be efficacious in the treatment of variable subsets of SE including simple partial SE, refractory SE, and super-refractory SE [8, 9]. Efficacy of 75% was also demonstrated in a very difficult to treat subset of patient with nonconvulsive SE in post-anoxic patients. Systematic qualitative analysis of publications in use of PMP for status epilepticus revealed highly variable results in highly variable populations [10]. More homogeneous single-center outcomes are needed. In a multi-centered study looking at 52 patients receiving PMP for treatment of SE, PMP was the last drug added in 61.5 % of patients and a positive response attributed to PMP in 36.5% and PMP was well tolerated with minimal side effects and no discontinuation [11].

The mechanism of action unique to PMP may be key in its success in this disease state. Perampanel (PMP) is a selective noncompetitive AMPA receptor antagonist. Blockade of excitatory mechanisms become important in SE given that prolonged SE may result in postsynaptic internalization of GABA-A receptors and subsequent reduced efficacy of GABAergic drugs [12]. In addition, PMP is rapidly absorbed by the GI system and peak plasma concentrations are achieved as early as 0.5 hours (0.5-2.5hours) with 100% bioavailability; features which make the drug attractive even in its oral form in the treatment of SE.

Two studies (E2007-A001-024 and E2007-A001-023) in healthy recreational drug users evaluated safety and abuse potential of perampanel and submitted with PMP NDA (#202834) to the FDA. Data was established at 8mg, 24mg, and 36 mg in both studies (Table 1). Increasing the dose to 36 mg was not associated with significant safety or tolerability issues. [Somnolence and dizziness were the most common side effects. Hemodynamics (systolic blood pressure, diastolic blood pressure, and heart rate) were not impacted. Kidney and liver functions were also largely not impacted with the exception of a single-incident of liver enzyme elevation. In order to reach steady state, simulation data reveals that steady state is reached immediately with a 4-5:1 dosing (loading dose to maintenance dose) Thus, the established safety confirmed a 36 mg loading dose as safe and tolerable. Hence, the investigators have chosen this as the loading dose for our study. Given that this is not an FDA approved dosage or indication, the investigators have obtained FDA authorization as an investigational new drug (IND 157959) to conduct this study.