Perampanel,an AMPA receptor antagonist: From clinical research to practice in clinical settings

Epileptic seizures are refractory to treatment in approximately one‐third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first‐in‐class non‐competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic‐clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long‐term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add‐on perampanel resulted in median percent reduction in seizure frequency 23.3%‐34.5% and ≥50% responder rate 28.5%‐37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%‐35.6%; ≥50% responder rate 40.9%‐45.0%) and elderly people (reduction in seizure frequency 12.5%‐16.9%; ≥50% responder rate 22.2%‐42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%‐38.0%) and global populations. Perampanel has been extensively studied in real‐world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%‐75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real‐world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2‐4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.     

Efficacy,safety, and tolerability of perampanel in Asian and non‐Asian patients with epilepsy

People of different ethnic or racial backgrounds may experience variations in pharmacokinetic and pharmacodynamic responses to drug therapies. Our post hoc analysis evaluated the efficacy, safety, and tolerability of perampanel in Asian and non‐Asian populations with refractory focal seizures with or without focal to bilateral tonic‐clonic (FBTC) seizures. This analysis pooled data from 4 randomized, placebo‐controlled, phase‐3 studies involving patients aged ≥12 years who have focal seizures with or without FBTC seizures. Patients were receiving 2, 4, 8, or 12 mg perampanel (or placebo) by the end of a 6‐week titration period and for a further 13 weeks during the maintenance phase. Efficacy endpoints included median percent change in seizure frequency per 28 days, and 50% and seizure‐freedom responder rates relative to baseline. The median percent change in seizure frequency per 28 days from baseline was significantly greater than placebo for perampanel 8 and 12 mg (?31.1% and ?38.1% change, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (?21.1% [P = 0.0001], ?26.3% [P < 0.0001], and ?27.7% [P = 0.0001] change, respectively) in the non‐Asian population. The 50% responder rate relative to baseline was significantly greater than placebo for perampanel 8 and 12 mg (40.1% and 43.8%, respectively; each P < 0.0001) in the Asian population, and for perampanel 4, 8, and 12 mg (29.4% [P = 0.0002], 32.8% [P < 0.0001] and 34.5% [P = 0.0001]), respectively, in the non‐Asian population. Seizure‐freedom rate among all patients was 4.9%‐11.7% for perampanel 2, 4, 8, and 12 mg. The most frequently reported treatment‐emergent adverse events (TEAEs) across both populations were dizziness, somnolence, irritability, headache, and fatigue. The most common psychiatric TEAEs were aggression and irritability. Perampanel demonstrated a favorable and similar risk‐benefit profile in both Asian and non‐Asian populations with refractory focal seizures.     

吡仑帕奈治疗局灶性癫痫的研究进展

吡仑帕奈为第三代新型抗癫痫发作药物,通过非竞争性抑制α-氨基-3-羟基-5-甲基-4-异恶唑啉丙酸受体来发挥其抗癫痫发作作用。多个国家已批准用于≥4岁局灶性癫痫患者(伴或不伴继发全面性发作)的单药及添加治疗。该文总结了吡仑帕奈治疗局灶性癫痫患者的作用机制、药代动力学、疗效及不良反应等的相关文献,以期为临床医师治疗局灶性癫痫提供更多的药物选择,从而更好地为临床上合理化用药提供依据。[国际神经病学神经外科学杂志,2023,50(4):85-89]     

Tolerability and safety of perampanel: two randomized dose-escalation studies

Krauss GL, Bar M, Biton V, Klapper JA, Rektor I, Vaiciene‐Magistris N, Squillacote D, Kumar D. Tolerability and safety of perampanel: two randomized dose‐escalation studies. Acta Neurol Scand: 2012: 125: 8–15.
© 2011 John Wiley & Sons A/S. Objectives – To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non‐competitive AMPA antagonist, as adjunctive therapy for refractory partial‐onset seizures. Materials and methods – Two consecutive, randomized, double‐blind, dose‐escalation studies recruited adults (18–70 years) with uncontrolled partial‐onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8‐week dose‐titration, 4‐week dose‐maintenance) with placebo or perampanel (up to 4 mg/day, dosed once‐ or twice‐daily). In study 208, patients received placebo or perampanel once‐daily (up to 12 mg) for 16 weeks (12‐week titration, 4‐week maintenance). Results – Overall, 153 patients were randomized into study 206 (perampanel twice‐daily, n = 51; perampanel once‐daily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once‐daily, n = 38; placebo, n = 10). The highest dose in study 206 – 4 mg/day – was well tolerated, with similar proportions of patients tolerating once‐daily (82.4%) and twice‐daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥ 6 mg perampanel once‐daily in a Kaplan–Meier analysis. In both studies, the most common adverse events were CNS‐related; most were of mild/moderate severity. Conclusions – Perampanel was well tolerated across doses of 4–12 mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.     

Clinical experience of abrupt discontinuation of perampanel: a case series

With an elimination half‐life of 105 hours, perampanel (PER) allows a once‐daily dosing regimen. In pivotal trials, when PER was tapered, it was therefore usually discontinued abruptly. Thus, in our hospital we have always practiced abrupt cessation. In this case series, we investigated how long PER serum concentrations still remain measurable after abrupt discontinuation of PER and whether withdrawal symptoms, such as an increase in seizures or status epilepticus, occur. PER serum levels and the clinical course of 15 adult in‐patients were monitored for three weeks based on a retrospective study design following abrupt discontinuation of PER. After one week, PER was still detected in 13 of 15 patients, after two weeks in 10, and after three weeks in three. Neither a severe increase in seizure frequency nor status epilepticus occurred. However, modifications of the concomitant antiseizure drugs were necessary. The abrupt discontinuation of PER leads to a slow decrease in plasma concentration, thus resembling self‐evident gradual discontinuation of PER. In some cases, PER may still be measurable and thus clinically active even weeks after its discontinuation. Efficacy and safety of other antiseizure drugs can be estimated appropriately only thereafter.     

Perampanel in patients with brain tumor-related epilepsy in real-life clinical practice: a retrospective analysis

Introduction: Epilepsy occurs in 35–70% of patients with gliomas; glutamate plays a central role via AMPA-receptor activation, which is involved both in seizure activity and tumor growth. We conducted a retrospective study on brain tumor-related epilepsy patients (BTRE) treated with perampanel in add-on (PER) for 12?months, to evaluate efficacy and tollerability, according to real-life clinical practice.

Materials and methods: Medical records of eleven patients (9 males, mean age 54?years) with glioma and epilepsy treated with PER in add-on, for inadequate seizure control or adverse events (AEs) from previous antiepileptic drugs (AEDs) therapy, were reviewed. Data collected included: tumor history, molecular factors, systemic therapy, type and number of seizures and concomitant AEDs, and AEs.

Results: After 12?months of PER therapy, five patients were seizure-free, 4 had a seizure reduction ≥50% and the seizure frequency was unchanged in 2 patients. Responder rate was 81.8%. Two patients reported AEs; PER dose was reduced only in the one case. The final median dose of PER was 7.3?mg/day. We didn’t find statistically significant differences in the comparison between mean values pre, mean values post and the average of decreasing number of seizures related to: histology, presence/absence of chemotherapy, radiotherapy, progression disease, KPS, IDH1, MGMT.

Discussion: Despite the limitations due to small number of patients in a retrospective study, the high rate of responder and seizure-free patients suggest that PER could be a therapeutic option in BTRE. Prospective controlled studies are needed to confirm our data.