Perampanel: A Promising AMPA Receptor Antagonist for Epilepsy Treatment

General Description

Preclinical studies have shown that perampanel, an AMPA receptor antagonist, has potential as an antiepileptic drug. It has demonstrated antiseizure activity, selectivity for AMPA receptors, and the ability to inhibit seizure propagation. Perampanel has also shown synergistic effects when combined with other AEDs and has been effective in managing focal seizures. Additionally, it may have neuroprotective properties, reducing brain edema and preserving motor function in a rat model of traumatic brain injury. In clinical practice, perampanel has been approved as adjunctive therapy for focal seizures and primary generalized tonic-clonic seizures based on strong clinical evidence. It has shown significant efficacy in reducing seizure frequency and has been generally well-tolerated, with common side effects including dizziness and headache. Long-term data has demonstrated sustained clinical benefits and tolerability.

Figure 1. PeraMpanel

Preclinical Studies

Preclinical evaluation of perampanel, an AMPA receptor antagonist, has shown promising results in various epilepsy models. It has been found to have antiseizure activity and potential as an antiepileptic drug (AED). Perampanel is a noncompetitive AMPA receptor antagonist, which is considered more effective than competitive antagonists. In preclinical studies, perampanel demonstrated selectivity for AMPA receptors and did not affect NMDA receptors. Its precise mechanism of action is not fully understood yet. Perampanel showed protective effects against seizures in mice, with lower doses required compared to other AEDs like carbamazepine or valproate. Furthermore, in a rat model of refractory epilepsy, high-dose perampanel significantly reduced seizure severity, and when combined with other AEDs, it further reduced seizure severity. Perampanel also showed the ability to inhibit seizure propagation and increase seizure threshold. Combination therapy with perampanel and zonisamide exhibited a synergistic effect, increasing the afterdischarge threshold and reducing seizure severity and duration. At lower doses, this combination was well-tolerated and highly efficacious for managing focal seizures. Perampanel has also shown efficacy in treating resistant focal seizures in a mouse model, whereas other medications like phenytoin did not produce the same antiseizure effect. Animal studies suggest that perampanel may be useful in stopping benzodiazepine-refractory status epilepticus (SE). In addition to its antiseizure effects, perampanel has shown potential neuroprotective effects in a rat model of traumatic brain injury (TBI). It reduced brain edema and contusion volume, preserved motor function, and attenuated cognitive dysfunction, neuronal apoptosis, oxidative stress, and inflammation. Although perampanel did not demonstrate neuroprotective effects in trials for multiple sclerosis and Parkinson's disease, its efficacy in TBI models suggests it may have anti-oxidative and anti-inflammatory properties. Overall, preclinical evaluation of perampanel has provided strong evidence of its antiseizure activity, potential synergistic effects in combination therapy, and possible neuroprotective properties. These findings support further research and clinical evaluation of perampanel as a potential treatment for epilepsy and related conditions. ¹

Clinical Practice

Focal seizures

Perampanel has been approved as adjunctive therapy for focal seizures with or without secondary generalization based on three phase-3 multicenter randomized controlled trials (RCTs) and an open-label extension study. Pooled analysis of 1478 patients with refractory epilepsy in the phase-3 RCTs showed that median changes in focal seizure frequency per 28 days and responder rates were significantly greater with perampanel at 4, 8, and 12 mg than with placebo. Median changes in complex focal plus secondarily generalized seizure frequency were also significantly greater with perampanel. The most common treatment-emergent adverse events (TEAEs) included dizziness, somnolence, headache, fatigue, and others, with most being mild to moderate in severity. Psychiatric TEAEs such as sleep disorder, anxiety, aggression, and confusional state were reported, with hostility/aggression events occurring more frequently with perampanel, although serious psychiatric AEs were uncommon. Long-term data from an open-label extension study demonstrated a median percent seizure reduction of 70.6% and a responder rate of 67.9% after 4 years of treatment with perampanel, with no new safety signals identified. ²

PGTC seizures

Perampanel has been approved for the treatment of primary generalized tonic-clonic (PGTC) seizures based on strong clinical evidence. In a study (study 332) focusing on patients with refractory PGTC seizures in idiopathic generalized epilepsy, perampanel 8 mg demonstrated significant efficacy compared to placebo. Patients treated with perampanel experienced a greater median percent change in PGTC seizure frequency per 28 days and a higher responder rate, with some achieving seizure freedom. The most common treatment-emergent adverse events (TEAEs) reported were dizziness, headache, and fatigue, indicating that perampanel was generally well-tolerated. Importantly, there was no indication that perampanel exacerbated absence or myoclonic seizures compared to placebo. Subsequent analyses showed favorable response rates for absence seizure freedom and myoclonic seizure freedom with perampanel. In a long-term open-label extension study lasting up to 2.5 years, perampanel continued to demonstrate significant reductions in PGTC seizure frequency and a high responder rate, maintaining its clinical benefits and tolerability over an extended period. ³

Reference

1. Potschka H, Trinka E. Perampanel: Does it have broad-spectrum potential?. Epilepsia. 2019;60:22-36.

2. Steinhoff BJ, Ben-Menachem E, Ryvlin P, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia. 2013;54:1481-1489.

3. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy a randomized trial. Neurology. 2015;85:950-957.