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A rapid and sensitive spectrofluorimetric method has been developed for the determination of perampanel in pharmaceutical preparations (assay method) and human plasma (bioanalytical method). The fluorescent product was measured at an excitation wavelength (λex) 294 nm and emission wavelength (λem) 430 nm. The assay method was validated as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2(R1) guidelines. For the assay method, the fluorescence intensity versus concentration plot was found to be linear over the concentration range 25–175 ng/mL.In case of bioanalytical method, for the extraction of drug from human plasma, a lucid liquid-liquid extraction method using ethyl acetate was employed. The bioanalytical method was validated according to the United States Food and Drug Administration (USFDA) guidelines and it was applied for the quantification of the drug in human plasma with reasonable accuracy and precision. For the bioanalytical method, the fluorescence intensity versus concentration plot was found to be linear over the concentration range 5–150 ng/mL. The impact of endogenous compounds of the plasma matrix on drug fluorescence was also assessed. To assess the greenness of the developed method, Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE) tools were applied and it was inferred that the developed method adheres closely to the principles of green analytical chemistry.

Perampanel (Fycompa®) is a non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonistic antiepileptic medication used to treat generalized seizure disorders. Very little is known about the management of patients following perampanel overdose, particularly in the pediatric population. We report a case of a pediatric patient, initially presenting with increased aggression and erratic behavior, who quickly developed severe respiratory failure and prolonged coma following an intentional ingestion of between 80 and 216 mg of perampanel (1.64–4.43 mg/kg of body weight). Phenobarbital was initiated to increase the metabolism of perampanel and for seizure prophylaxis. Perampanel toxicity has been associated with a range of symptoms including bradycardia, hypotension, hyponatremia, central nervous system depression, prolonged coma, hypercoagulable state, and erratic, aggressive “zombie-like” behavior. With a reported half-life of 105 hours, no known reversal agent, and limited evidence-based management, clinicians should be prepared for prompt resuscitation and prolonged management of patients with suspected perampanel intoxication. Educational Objectives: 1. Identify symptoms of perampanel overdose and consider early intubation and resuscitation for prolonged coma and respiratory failure. 2. Describe alternative methods to increase metabolization of medications with prolonged half-life.

Objectives: The centrifugal ultrafiltration–high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method was established to determine the free perampanel (PER) concentration in children with epilepsy. Methods: Free PER concentration was obtained using centrifugal ultrafiltration devices. The internal standard was PER-D5. The method was investigated for selectivity, carryover, lower limit of quantification, calibration curve, accuracy, precision, matrix effects, recovery, and stability. The Spearman's correlation coefficient was used to evaluate the correlation between the free and total PER concentrations. A nonparametric test was used to estimate the effects of PER along with other antiepileptic drugs on the total and free PER concentrations. Results: The free PER concentration was positively correlated with the total PER concentration in the 57 plasma samples (r = 0.793 > 0, P

Background: Since 2019, Perampanel (PER) has been endorsed in China as an adjunctive treatment for focal seizures, both with and without impaired awareness, and for the transition from focal to bilateral tonic-clonic seizures. Limited research exists regarding the efficacy of PER in treating post-stroke epilepsy (PSE) in China. Empirical studies are essential to guide treatment protocols. We conducted a retrospective study to assess the efficacy and tolerability of PER in 58 PSE patients treated between October 2019 and July 2023. Method: This study encompassed 58 patients with PSE, treated with PER either as monotherapy or as part of adjunctive therapy, and underwent follow-up for a minimum duration of 6 months. The study assessed changes in seizure frequency, adverse events (AEs), drug retention rate, maintenance dose, and adverse reactions following PER treatment. Results: The study included 58 PSE patients, with 60.3% males and 39.7% females, ranging in age from 18 to 89, mostly within the 61–70 age group. Ischemic strokes constituted 58.6% of cases, while hemorrhagic strokes accounted for 41.4%. Focal seizures, either with or without impaired awareness, were noted in 62.1% of patients, and a transition from focal to bilateral tonic-clonic seizures was seen in 32.8%. The retention rates for PER at 3 and 6 months stood at 94.8% and 84.5% respectively, and the most commonly administered maintenance dose was 4 mg/day (41.28%). In the adjunctive therapy group, efficacy rates were 66.7% at 3 months and 78.6% at 6 months, compared to 80.0% at 3 months and 85.7% at 6 months in the monotherapy group. In the efficacy analysis, with a criterion of ≥50% reduction in seizure frequency, the overall efficacy rates at 3 and 6 months were 69.1% and 79.6%, respectively. Adverse reactions occurred in 46.6% of patients, primarily involving irritability and somnolence (both 27.6%), with no marked difference in incidence between the adjunctive and monotherapy groups (P > 0.05). Conclusion: PER exhibits favorable efficacy and tolerability in Chinese PSE patients, possibly at lower doses.

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects.

Background: Perampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. Method: We analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. Results: Overall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. Conclusion: PER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The current study aimed to investigate the low dose perampanel (PER) (0.125 and 0.5 mg/kg) and pregabalin (PG) (15 mg/kg) as standalone treatments and in combination on kindling-induced seizure progression with concurrent electroencephalographic alterations. Mice were subjected to pentylenetetrazole (PTZ)-induced kindling followed by neurobehavioral assessment for anxiety-like activity and cognitive deficit through behavioral experiments. The monotherapy with PER at 0.5 mg/kg and PG at 15 mg/kg delayed the kindling process but PRP+PG yielded pronounced benefits and hindered the development of seizures of higher severity. PER+PG combination relieved the animals from anxiety-like behavior in various employed anxiogenic tests. Furthermore, the kindling-associated cognitive deficit was protected by PER+PG combination as increased alteration behavior, discrimination index and latencies to enter the dark zone were noted in y-maze, object recognition and passive avoidance tests, respectively while shorter escape latencies were noted in water maze. The brain samples of kindled mice had elevated malondialdehyde and reduced catalase, superoxide dismutase and glutathione peroxidase enzymes while treatment with PER and PG combination shielded the mice from heightened kindling-associated oxidative stress. Overall, the findings of the present study illustrate that concurrent administration of PER and PG effectively hindered the process of epileptogenesis by protecting neuronal excitability and brain oxidative stress. The results predict the dominance of PER and PG combination over monotherapy which might serve as an effective novel combination to combat drug resistance and behavioral disorders in epileptic patients.

Purpose: To observe the efficacy, safety, and tolerability of perampanel (PER) as add-on therapy in children aged 4-18 years with epilepsy in a real-world environment., Methods: A single-center, retrospective, observational study was conducted at the First Affiliated Hospital of Fujian Medical University enrolling children with epilepsy aged 4-18 years who received PER as add-on therapy from January 2021 to November 2022 with 12 months of follow-up. Outcomes included 3-, 6- and 12-month retention, seizure freedom, responder rates, and adverse events (AEs) throughout follow-up., Results: Seventy-eight children were included, of whom three were lost to follow-up. The responder rate at follow-up of 12 months was 54.7 %, the seizure-free rate was 32.0 % and the retention rate was 81.3 %. The number of seizures at baseline was a factor influencing the efficacy of the PER. Nine children reported AEs, with dizziness, drowsiness, and irritability being common., Conclusions: PER is safe, effective, and well tolerated for the treatment of children aged 4-18 years with epilepsy in clinical practice and is a potential option for refractory epilepsy. Patients with lower baseline seizure frequencies are more likely to exhibit a favorable response to PER., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This post-hoc analysis of the PERMIT Extension study compared the effectiveness and safety/tolerability of perampanel (PER) between Asian and non-Asian participants. Retention rates, adverse events (AEs), seizure frequency, responder rate (≥50% seizure frequency reduction), and seizure freedom rate (no seizures since at least the prior visit) were assessed. Retention was assessed after 3, 6 and 12 months. Effectiveness assessments were evaluated at 3, 6 and 12 months and the last visit by seizure type (total, focal and generalised). PERMIT Extension included 730 Asian and 1662 non-Asian individuals. Significant differences in demographic/baseline characteristics were reported for the Asian versus non-Asian subgroups including higher median age at epilepsy onset, longer median duration of epilepsy, higher mean number of previous and concomitant ASMs and lower mean monthly seizure frequency (total, focal and generalised). Retention rates were similar between the two subgroups at 3 and 12 months, but significantly lower in the Asian versus non-Asian subgroup at 6 months (65.6% vs. 71.8%; p = 0.004). At last visit, seizure freedom rate was significantly higher in the Asian versus non-Asian for total (35.9% vs. 25.4%; p = 0.001) and focal seizures (32.4% vs. 18.9%; p = 0.001) as was responder rate for both total (63.9% vs. 52.3%; p = 0.001) and focal seizures (62.2% vs. 44.7%; p < 0.001). Seizure freedom and responder rates for generalised seizures were similar between the two subgroups at the last visit. Rates of AEs were similar between the two subgroups (Asian, 47.6%; non-Asian, 45.4%). PER was effective and generally well-tolerated in Asian and non-Asian individuals., Competing Interests: Declaration of competing interest TA has received consultancy fees, speaker fees, and research grants from Novartis, Eli Lilly, GlaxoSmithKline, Lundbeck, Pfizer, Hikma and AbbVie. KK has received consultant fees and speaker fees from Eisai, UCB Japan and Daiichi-Sankyo. AD is an employee of Eisai Singapore Pte. Ltd. SC is an employee of Eisai, Inc. VV has participated in advisory boards and symposia organised by Angelini, Bial, Biocodex, Eisai Inc., Jazz Pharmaceuticals, Novartis, Takeda, UCB and Xenon. DWK, HG, YC and TW have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background: Perampanel, the first third-generation anti-seizure medication targeting the AMPA receptor, has been used in the treatment of patients with focal seizures, with or without secondary generalized seizures, and primary generalized tonic-clonic seizures. This study focused on the effectiveness and safety of perampanel for pediatric patients with at least 1-year follow-up in real-world settings., Methods: We systematically searched PubMed, EMBASE, and Web of Science for real-world studies published before April 27, 2024. The data of interest were extracted and analyzed using the R software (version 4.2.1)., Results: From 1181 retrieved citations, 25 records involved a total of 2985 individuals were included in the meta-analysis. The 50 % responder rate pooled from the 22 studies yielded an overall 55.0 % (95 % CI: 46.1-63.8 %), with significant evidence of between-study heterogeneity (I 2 = 93 %, P < 0.01, τ 2 = 0.038). The seizure-free rate pooled from 22 studies yielded an overall rate of 28.9 % (95 % CI: 19.6-39.1 %). Twenty studies reported the retention rate of perampanel treatment with a pooled proportion was 71.1 % (95 % CI: 61.1-80.2 %). The estimate of the adverse events incidence rate pooled from the 23 studies yielded an overall 29.0 % (95 % CI: 23.4-34.9 %). Subgroup analyses were conducted based on follow-up time (12 months or ≥ 24 months)., Conclusion: Perampanel is generally well tolerated and effective in the treatment of epilepsy in children and adolescents with mid-long-term follow-up. The 50 % responder rate in children and adolescents improved with time. The retention rate and the seizure-free rate during at least 24 months of follow-up were not as sustained as those in 12 months of follow-up. Adverse events, particularly psychiatric and behavioral, should be monitored during clinical practice administration., Competing Interests: Declarations of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The new antiepileptic drugs perampanel, retigabine, rufinamide and stiripentol have been recently approved for different epilepsy types. Being them an innovation in the antiepileptics armamentarium, a lot of investigations regarding their pharmacological properties are yet to be performed. Besides, considering their broad anticonvulsant activities, an extension of their therapeutic indications may be worthy of investigation, especially regarding other seizure types as well as other central nervous system disorders. Although different liquid chromatographic (LC) methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection have already been developed for the determination of perampanel, retigabine, rufinamide and stiripentol, new and more cost-effective methods are yet required. Therefore, this review summarizes the main analytical aspects regarding the liquid chromatographic methods developed for the analysis of perampanel, retigabine (and its main active metabolite), rufinamide and stiripentol in biological samples and pharmaceutical dosage forms. Furthermore, the physicochemical and stability properties of the target compounds will also be addressed. Thus, this review gathers, for the first time, important background information on LC methods that have been developed and applied for the determination of perampanel, retigabine, rufinamide and stiripentol, which should be considered as a starting point if new (bio)analytical techniques are aimed to be implemented for these drugs.

Pathogenic variants in gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) is a protein coding gene that has been associated with a broad phenotypic spectrum of epilepsies. These have ranged from mild generalized forms to early-onset severe epileptic encephalopathies. Both in mild and in severe forms, tonic-clonic and myoclonic seizures with generalized spike and wave discharges and photoparoxysmal responses are common clinical manifestations. We present the case of a 14-year-old girl referred to our clinic with uncontrolled epilepsy. She was found to carry a heterozygous variant (c.335G > A) in GABRA1, already described in the literature and classified as “pathogenic” according to ACMG guidelines. The patient showed severe drug resistance with seizures often triggered by photic stimulation. The introduction of perampanel therapy led to overall reduction of the focal and generalized myoclonic seizures and complete clinical control of the light-triggered seizures.To our knowledge this is the first report of perampanel efficacy in photosensitive epilepsy, and in particular in the presence of a GABRA1 variant. New evidence is needed to confirm our findings in this case.

Objective: Giant somatosensory evoked potentials (SEPs) are observed in patients with cortical myoclonus. Short-latency components (SLC), are regarded as evoked epileptic activities or paroxysmal depolarization shifts (PDSs). This study aimed to reveal the electrophysiological significance of the middle-latency component (MLC) P50 of the SEPs., Methods: Twenty-two patients with cortical myoclonus having giant SEPs (patient group) and 15 healthy controls were included in this study. Waveform changes in SEPs before and after perampanel (PER) treatment were evaluated in the patient group. The wide range, time-frequency properties underlying the waveforms were compared between the groups., Results: After PER treatment, SLC was prolonged and positively correlated with PER concentration, whereas MLC showed no correlation with PER concentration. Time-frequency analysis showed a power increase (156 Hz in all patients, 624 Hz in benign adult familial myoclonus epilepsy patients) underlying SLC and a power decrease (156 Hz, 624 Hz) underlying MLC in the patient group., Conclusions: The high-frequency power increase in SLCs and decrease in MLCs clearly reflected PDS and subsequent hyperpolarization, respectively. This relationship was similar to that of interictal epileptiform discharges, suggesting that giant SEPs evoke epileptic complexes of excitatory and inhibitory components., Significance: MLCs of giant SEPs reflected inhibitory components., (Copyright © 2024. Published by Elsevier B.V.)

Objective: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy., Methods: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up., Results: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ± 328.1 ng/mL, in contrast to the CC phenotype at 334.0 ± 161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625-900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy., Conclusion: The CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. The authors confirm that they have read the Journal's policy on issues involved in ethical publication, and affirm that this study is consistent with those guidelines., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Temporal Lobectomy (TL) is an accepted surgical procedure for refractory seizures. Aims: To assess the effects of Perampanel (PER) therapy in patients with refractory temporal lobe epilepsy. Methodology: Perampanel therapy was administered in two cases with refractory seizures post temporal lobectomy and in two others with refractory seizures who were eligible for temporal lobectomy. Results: There was significant control in seizures in all the four cases with Perampanel as a single add on to ongoing refractory state.

We report a retrospective monocentric study performed on 63 patients affected by epilepsy with known etiology, receiving perampanel as add-on therapy with at least 12-month follow-up. The purpose of our study was to evaluate efficacy and tolerability of perampanel in this group of epilepsies. Patients were classified into 2 groups based on the presence/absence of a single focal brain lesion on MRI, as epilepsy etiology: 48 subjects were affected by focal lesional epilepsy and 15 by non-focal lesional epilepsy. The retention rate was 76.2% and 53.9% at 12 and 24 months respectively. At 12 months, at least 40% of patients resulted responders, with a significant reduction in seizure frequency (p = 0.01), confirmed at 24 months. Considering epilepsy etiology, we found a better PER response in patients with focal lesional epilepsy. A significant correlation was observed between responder rates and EEG pattern. Only 30% of patients reported mild-moderate adverse events. Efficacy and tolerability of PER, in our study, are in line with the results reported in other real-world studies. Our data suggest the possibility of better PER response in patients with focal brain lesions, which indicates that this drug could be a therapeutic option in this population.

Perampanel (PER) is approved in Italy as an adjunctive treatment for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCs), and it could be an alternative to valproate in young women diagnosed with idiopathic generalized epilepsy. Nevertheless, clinical data about the outcome of pregnancies in women exposed to PER are lacking. Here, we report retrospectively collected data from four women suffering from FOS who were exposed to PER during pregnancy. Three pregnancies were carried out with PER as add-on therapy during the entire gestation (8 mg/day in two patients and 6 mg/day in one), without seizure frequency variations. The fourth patient started PER 2 mg/day as monotherapy during the 13th week of pregnancy due to seizure relapse and continued it until delivery with complete seizure control. All pregnancies showed good outcomes, and their newborns did not possess major congenital malformations. Apgar scores and auxological parameters at birth were normal. Fetal pathology in follow-up during pregnancies was absent in all cases. In our patients PER was well tolerated and appeared safe for the fetuses and did not result in major malformations or adverse events at birth. Nevertheless, this is a report involving a small number of patients and it does not suggest the general use of PER is safe during pregnancy.

Objectives: This study aimed to identify clinical characteristics that could predict the response to perampanel (PER) and determine whether structural connectivity is a predictive factor., Methods: We enrolled patients with epilepsy who received PER and were followed-up for a minimum of 12 months. Good PER responders, who were seizure-free or presented with more than 50 % seizure reduction, were classified separately from poor PER responders who had seizure reduction of less than 50 % or non-responders. A graph theoretical analysis was conducted based on diffusion tensor imaging to calculate network measures of structural connectivity among patients with epilepsy., Results: 106 patients with epilepsy were enrolled, including 26 good PER responders and 80 poor PER responders. Good PER responders used fewer anti-seizure medications before PER administration compared to those by poor PER responders (3 vs. 4; p = 0.042). Early PER treatment was more common in good PER responders than poor PER responders (46.2 vs. 21.3 %, p = 0.014). Regarding cortical structural connectivity, the global efficiency was higher and characteristic path length was lower in good PER responders than in poor PER responders (0.647 vs. 0.635, p = 0.006; 1.726 vs. 1,759, p = 0.008, respectively). For subcortical structural connectivity, the mean clustering coefficient and small-worldness index were higher in good PER responders than in poor PER responders (0.821 vs. 0.791, p = 0.009; 0.597 vs. 0.560, p = 0.009, respectively)., Conclusion: This study demonstrated that early PER administration can predict a good PER response in patients with epilepsy, and structural connectivity could potentially offer clinical utility in predicting PER response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Perampanel (PER) is a new anti-seizure medication (ASM) with a novel mechanism of action. This study aimed to determine the efficacy and safety of PER when added to monotherapy in children and adolescents (age, 4-18 years) with epilepsy., Method: A multicenter prospective observational study was performed on children and adolescents (age, 4-18 years) with epilepsy who did not respond to ASM monotherapy between July 2021 and October 2022. PER was used as the first add-on therapy for the enrolled patients. Seizure-free rate, response rate, inefficacy rate, and drug retention rate were the main observation indicators during the 6 months of treatment. The patients were grouped based on treatment efficacy, and factors affecting efficacy were statistically analyzed. Adverse reactions were also recorded., Results: In this study, 93 patients with epilepsy were enrolled; among them, 9 patients were lost to follow-up (attrition rate, 9.7 %), and 84 were included in the analysis. Five patients with unknown efficacy discontinued taking PER early due to intolerable adverse reactions, and 79 patients (48 males, 31 females; mean age, 11.0 ± 3.9 years) finally remained. Genetic epilepsy and structural epilepsy were found in 22 patients and 36 patients, respectively. The mean duration of epilepsy history at the time of PER initiation was 4.0 ± 3.8 years, and the mean maintenance dosage of add-on PER was 4.5 ± 1.8 mg/day (equivalent to 0.14 ± 0.07 mg/kg/day). Among the 79 patients, 28 patients were diagnosed with epilepsy syndrome, including 13 patients having self-limited epilepsy with centrotemporal spikes, among whom 9 patients were seizure-free after adding PER during the 6-month follow-up (seizure-free rate, 69.2 %). For these 79 patients, the seizure-free, response, and retention rates at the end of follow-up were 45.6 %, 74.7 %, and 82.1 %, respectively. Among the 84 patients included in the analyses, adverse reactions occurred in 20 patients, mainly dizziness (8 patients), somnolence (6 patients), and irritability (4 patients), and 4 patients developed two adverse reactions simultaneously. Univariate analyses revealed statistically significant differences in efficacy between groups with structural and non-structural epilepsy and between groups with different baseline concomitant ASMs, suggesting that these factors affected the efficacy of PER as the first add-on therapy., Conclusion: The overall response rate of PER as the first add-on therapy for children and adolescents with epilepsy who were followed up for 6 months was 74.7 %, indicating a relatively favorable safety and tolerability profile. The group of the baseline concomitant ASM administered and the etiological classification of epilepsy as either structural or non-structural were the factors influencing the efficacy of PER as the first add-on therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

We present a simple and fast high-performance liquid chromatography method with fluorescence detection for the determination of the antiepileptic drug perampanel in human plasma. The chromatographic separation was performed on a Kinetex PFP (100 × 2.6 mm, 4.6 µm) column, using a mobile phase of sodium acetate 0.03 M pH 3.7 and acetonitrile (40/60, v/v), at a flow rate of 0.8 mL/min. Total chromatography time for each run was 5 min. Sample preparation (250 µL) involved only one simple precipitation step by acetonitrile spiked with mirtazapine as internal standard. The method was validated over a concentration range of 20–1000 ng/mL and successfully applied to measure perampanel concentrations in plasma samples obtained from patients with epilepsy. This assay combines the high specificity of fluorescence detection with a very simple and fast sample pretreatment and can offer real advantages over existing methods in terms of simplicity and transferability to a therapeutic drug monitoring setting.

Background: To analyze the efficacy and safety of perampanel over a 3-month period in a sample of Asian people with epilepsy. Methods: The efficacy and safety of perampanel as an adjunctive therapy for patients with epilepsy were retrospectively reviewed and analyzed. Patients were categorized according to seizure type, concomitant antiepileptic drug usage, and perampanel dosage. Results: A total of 210 patients were included in the study and 131 patients completed 3 months of perampanel treatment. The average dosage of perampanel was 5.31 mg/day, and the 50% responder rate (≥50% seizure frequency reduction) in all patients was 45.8%, with a 27.5% seizure-free rate. For focal seizures, focal to bilateral tonic-clonic seizures, and primary generalized seizures, the 50% responder rates were respectively 29.4%, 49.5%, and 36.4%. In total, 39.5% of patients experienced adverse events within 3 months of observation period, and the rate of drug withdrawal due to adverse events was 8.6%. Dizziness, ataxia, irritability/aggression were the most common adverse events. Conclusions: The efficacy and safety of perampanel in a real-world setting with Asian patients is comparable to that in clinical trials that have included fewer Asian patients.

Perampanel is the first-in-class selective and noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. It is authorized in the U.S. and Europe as an add-on antiepileptic drug for partial-onset seizures, and for primary generalized tonic–clonic seizures. Single reports have also indicated a potential efficacy for myoclonic jerks. Here, we report a patient whose drug-resistant epilepsia partialis continua completely resolved after adding perampanel. She has remained seizure-free in an eighteen-month follow-up period. Epilepsia partialis continua reemerged transiently after perampanel was temporarily discontinued, with no recurrence after its reintroduction. Therefore, this effect was reproducible, and suggests that it might be worth trying perampanel in similar settings.

We administered perampanel (PER) to a bedridden 13-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA). The DRPLA diagnosis was based on the presence of a CAG trinucleotide repeat in the ATN1 gene. The patient experienced continuous myoclonic seizures and weekly generalized tonic–clonic seizures (GTCs). PER stopped the patient's myoclonic seizures and reduced the GTCs to fragmented clonic seizures. The patient recovered his intellectual abilities and began to walk again with assistance. We suggest that PER be considered as one of the key drugs used to treat patients with DRPLA.

Proper treatment of hypoxic myoclonic status is not clearly determined. Induced hypothermia is improving prognosis and a more aggressive treatment might be beneficial in some patients. Among the new options of antiepileptic drugs, perampanel (PER) is a drug with a novel mechanism, and it might be a promising drug for myoclonic status or as an antimyoclonic drug. We describe the use of PER in one patient with hypoxic super-refractory myoclonic status. Description: A 51-year-old patient presented after an out-of-hospital cardiac arrest due to an acute myocardial infarction. The patient was diagnosed with clinical and electrical (EEG) myoclonic status at the rewarming phase. Several treatments were used, starting with clonazepam, valproate, sedation (midazolam, propofol), and subsequently barbiturate-induced coma with persistent myoclonic status. Finally, we decided to try PER (dose: 6–8 mg) through a nasogastric tube, resulting in a marked improvement of EEG activity and myoclonus decrease. The patient had a progressive clinical improvement, with a CPC (Cerebral Performance Category) scale score of 1. Conclusion: This case shows the potential utility of PER as a therapeutic option in super-refractory hypoxic status and even its potential use before other aggressive alternatives considering their greater morbidity.

Objective: To assess the effectiveness and tolerability of perampanel (PER) monotherapy in real-world practice for the treatment of focal-onset seizures (FOS) in eastern China., Method: This is a single-center, retrospective study of patients with FOS, aged ≥ 4 years, who had been prescribed PER as monotherapy. Outcomes included retention, seizure-free, and responder rates at 3, 6 and 12 months and adverse events (AEs) throughout the follow-up period. The efficacy and AEs of PER monotherapy in patients with aged < 14 years old and ≥ 14 years old were also compared., Results: Sixty-seven patients with FOS who received PER monotherapy and completed a one-year follow-up were included in the analysis. The median maintenance dose was 4 mg. Modified intent-to-treat analysis demonstrated that the retention rates of PER monotherapy at follow-up of 3, 6 and 12months were 75%, 70% and 63%, respectively. At the same points, seizure-free rates of PER monotherapy were 69%, 63% and 52%, and responder rates were 69%, 66% and 61%, respectively. Patients with sleep-related seizures had higher seizure-free rates at 12 months of follow-up. No significant difference in seizure-free and responder rates was found between the aged < 14 years old and the aged ≥ 14 years old. Twenty-one patients (31.3%) had AEs and five patients discontinued using PER because of intolerant AEs. Common AEs were dizziness, irritability and somnolence. The AEs rate in patients < 14 years was 17.9%, significantly lower than patients ≥ 14 years., Conclusions: Our findings revealed the real-world data of patients in eastern China with FOS using PER as monotherapy. Patients had good retention, seizure-free and responder rates, and relatively low AEs rate at a low dose of PER treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Lafora disease is a rare and fatal disease characterized by seizures, progressive cognitive and behavioral deterioration, as well as cerebellar dysfunction. Currently, there is no efficacious treatment that will control the seizures and improve the cognitive decline in this disease. We report a patient with Lafora disease who experienced a dramatic amelioration in her seizure frequency as well as the associated neurological and cognitive dysfunction following initiation of treatment with perampanel administered as monotherapy. Perampanel is the first potentially efficacious treatment for Lafora disease. We discuss a potential mechanism for the efficacy of perampanel in this disease.

Objective: Perampanel (PER) is a novel antiepileptic drug. The efficacy, tolerability and safety of PER in children and adolescents with epilepsy are still unclear. We aimed to study the efficacy and safety of PER in children and adolescents with epilepsy., Methods: We searched PubMed, Embase and Cochrane Library for relevant literature up to November 2022. Then we extracted the relevant data from eligible literature for systematic review and meta-analysis., Result: Twenty-one studies involving 1968 children and adolescent patients were included. A reduction in seizure frequency of at least 50 percent occurred in 51.5% (95% confidence interval [CI] [47.1%, 55.9%]) of patients. Complete seizure cessation occurred in 20.6% (95%CI [16.7%, 25.4%]). The incidence of adverse events was 40.8% (95%CI [33.8%, 48.2%]). The most common adverse events were drowsiness 15.3% (95% CI [13.7%, 16.9%]), irritability 9.3% (95%CI [8.0%, 10.6%]), dizziness 8.4% (95% CI [7.2%, 9.7%]). The incidence of drug discontinuation due to adverse events was 9.2% (95% CI [7.0%, 11.5%])., Conclusion: PER is generally well tolerated and effective in the treatment of epilepsy in children and adolescents. Larger studies are still needed to explore the application of PER in children and adolescents., Risk of Bias and Limitation: The funnel plot suggests that there may be publication bias in our meta-analysis, and most of the included studies were Asian, so there may be some racial differences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the safety of perampanel in different disorders and doses., Methods: Embase, the Cochrane Library, Medline, and ClinicalTrials.gov were searched from inception to July 2022 for randomized controlled trials (RCTs). The meta-analysis was performed by using Review Manager 5.3 and R 4.2.1 software., Results: A total of 17 RCTs with 5711 subjects were included in the final analysis. The double-blind treatment phase was from 12 weeks to 48 weeks. Our results showed that 11 adverse events (aggression, ataxia, balance disorder, dizziness, fall, fatigue, irritability, rash, somnolence, vertigo, and weight increase) were statistically significantly associated with perampanel, and 4 of them (ataxia, dizziness, fatigue, and somnolence) showed a clear dose-response relationship. Psychiatric adverse events occurred most frequently among serious treatment-emergent adverse events (TEAEs). At 8 mg/day, seven adverse events (aggression, balance disorder, dizziness, fatigue, irritability, vertigo, and weight increase) occurred more frequently in patients with epilepsy than in patients with other disorders, whereas dose discontinuation rates due to adverse events were lower in patients with epilepsy than in patients with other disorders., Conclusion: The safety profile of perampanel is dependent on diseases and dose. The risk of adverse events was statistically significantly higher, with doses exceeding 4 mg/day. Despite a higher risk of adverse events, patients with epilepsy had a lower perampanel discontinuation rate than patients with other disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Perampanel a third-generation antiseizure medication, belongs to a new promising class of drugs called AMPA receptor antagonists, approved to treat focal-onset seizures with or without focal to bilateral tonic clonic seizures and primary generalized tonic-clonic seizures., Methods: This review included RCTs on patients with epilepsy exposed to perampanel compared with placebo, or one or more pre-existing antiseizure medications. Four databases and two clinical trial registries were searched from inception to July 2021. Included outcomes were 50% responder rate, seizure-free rate, discontinuation due to treatment-emergent adverse events (TEAE)s, having any TEAEs, and most reported TEAEs. Cochrane risk of bias tool was used to assess the internal validity of the included RCTs., Results: From 2211 retrieved citations, eight RCTs were included in the meta-analysis. Fifty-percent responder and seizure freedom rates were significantly higher in patients receiving perampanel when compared to placebo (RR 1.57, 95 % CI 1.35 to 1.82, I 2 15% and RR 2.79, 95% CI 1.58 to 4.93, I 2 7%, respectively). The 50% responder rates for 8mg and 12 mg, when compared to placebo, were similar. The most-reported TEAEs were dizziness and somnolence with <1% reporting serious psychological outcomes., Conclusion: This systematic review reports significant reduction in seizures and a potential dose-based increase in discontinuations due to TEAE. The most-reported TEAEs were non-threatening, with the possibility of rare but serious adverse psychological outcomes. Further independent RCTs studying the most efficient dose for efficacy and safety are needed., Competing Interests: Declaration of Competing Interest No authors have conflicts of interest to disclose., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study., Methods: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs., Results: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency [interquartile range], 1.7 [1.0-10.0]; mean [standard deviation] prior antiseizure medications, 2.9 [2.6]). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months., Conclusion: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: To evaluate the effectiveness and tolerability of perampanel (PER) in real-world settings in patients between 1 month and 18 years of age with drug resistant epilepsy (DRE) waiting for epilepsy surgery., Methods: In this multicenter study, patients between 1 month and 18 years of age with DRE treated with PER between January 2020 and June 2021 were selected. The study outcome was effectiveness of PER treatment reported as reduction in seizure frequency and seizure freedom rate. Effectiveness was assessed at 30, 60, 90, 120, 150 and 180 days after initiation of PER. Tolerability profiles were reported as adverse events according to the observations of the patients' family members and physician., Results: Eighty-five patients treated with PER were included in the study. The mean initial dose and mean maximum dose of adjunctive PER was 2 mg/day and 5.8 mg/day, respectively. The mean seizure frequency (rate/week) was 41.3, 25.4, 18.9, 14.3, 11.2, 11.1 and 8.9 seizures at baseline, 30, 60, 90, 120, 150 and 180 days, respectively; the reduction in the mean seizure frequency at all timepoints was significant compared at the baseline (p<0.001). At 180 days, ≥75% seizure reduction was seen in 64.9% (37/57) of the patients and seizure freedom was achieved in 36.8% (21/57). Drowsiness, ataxia, and behavioral changes were the common adverse events observed, and these improved after the dose of PER was reduced. No discontinuation of PER was required due to side effects or intolerance., Conclusion: In real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Report final data from adolescent (12-<18 years) and adult (≥18 years) patients from PROVE (NCT03208660), a multicenter, retrospective, non-interventional, Phase IV study to assess retention, efficacy, safety, and dosing of perampanel in patients with epilepsy during routine clinical care., Methods: Data were retrospectively collected from medical/pharmacy records of patients in the US initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary endpoints included median percent changes in seizure frequency, seizure-freedom rates, investigator's impression of seizure effect, and treatment-emergent adverse events (TEAEs)., Results: The Safety Analysis Set (SAS) included 294 adolescents and 1157 adults (median maximum perampanel dose, 6.0 mg/day). In patients eligible for inclusion in the retention rate analysis, 24-month retention rates were 53.5% (n=91/170) in adolescents and 47.8% (n=354/741) in adults. In patients with available efficacy data during Months 10-12, median percent seizure frequency reductions were 79.3% (n=20) in adolescents and 70.8% (n=92) in adults. Most patients in the SAS with seizure-effect data experienced an improvement in seizures at the last follow-up time point (adolescents, 51.4% [n=128/249]; adults, 52.3% [n=506/967]). TEAEs occurred in 113 adolescents (38.4%; most common, aggression [6.5%]) and 512 adults (44.3%; most common, dizziness [9.2%])., Conclusion: Perampanel demonstrated favorable retention rates and sustained efficacy (up to 2 years) in adolescent and adult patients during routine clinical care; no new safety signals were observed., Gov Identifier: NCT03208660 (https://clinicaltrials.gov/ct2/show/NCT03208660)., (Copyright © 2022. Published by Elsevier Ltd.)

Temporal lobe epilepsy (TLE) has a low antiepileptic drug (AED) treatment response rate, and about 70% of patients eventually progress to refractory epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, which is used clinically for the treatment of partially refractory epilepsy, but its mechanism of action is not completely clear. In this study, kainic acid (KA) was successfully used to induce TLE in 3-week-old C57BL/6 immature mice, and the effects of PER on the cognitive behavior of the epileptic mice were characterized using the Morris water maze paradigm. To determine the mechanism underlying the therapeutic effects of PER, the morphological evolution of the hippocampus and the expression of AP-1 and GluR1 were systematically evaluated. Compared to control TLE mice, escape latency was reduced and the number of target platform crossings was increased in the Morris water maze by treatment with PER. The therapeutic effects of PER were mediated mainly via inhibition of the expression of AP-1 and GluR1, as the TLE mice showed significantly improved learning and memory and decreased seizure frequency after treatment with PER., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Perampanel is a new antiepileptic used to treat partial-onset seizures and generalized tonic-clonic seizures in people older than 12 years old. Perampanel is a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, with a prolonged half-life of approximately 105 hours. Few cases of significant toxicity have been reported, and effects in overdose are poorly understood., Case Report: This case describes a 20-month-old healthy female who ingested 8 mg of perampanel. She presented to a pediatric emergency department 1 hour after ingestion with ataxia, irritability, and somnolence. Vital signs were: heart rate 130 beats per minute, blood pressure 112/97 mmHg, temperature 99°F, respiratory rate 30 breaths per minute. She was admitted to the pediatric intensive care unit. During the hospitalization, she developed hypotension and bradycardia which improved with stimulation and fluid resuscitation. Intermittent bradycardia persisted for 32 hours after ingestion. Physical examination was notable for somnolence and truncal ataxia with irritability when aroused, all of which improved throughout the hospitalization. A quantitative level obtained on hospital day 3 (HD) was 750ng/ml. On HD 3 the patient was noted to be ataxic but otherwise had an age-appropriate neurologic examination. She was discharged on HD 4 with normal vital signs, return to baseline mental status, and baseline gait. The patient's cardiovascular, neurologic, and behavioral symptoms were attributed to perampanel toxicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS ?: Toxicity from a perampanel overdose is poorly understood both in adults and pediatric patients with significant cardiovascular, behavioral, and central nervous system abnormalities., (Published by Elsevier Inc.)

Objective: Quantitative Encephalography (qEEG) depicts synthetically the features of EEG signal and represents a promising tool in the assessment of neurophysiological changes brought about by Anti-Seizure Medications (ASMs). In this study we characterized qEEG alterations related to add-on therapy with Perampanel (PER). PER is the only ASM presenting a direct glutamatergic antagonism, hence the characterization of PER induced EEG changes could help to better understand its large spectrum of efficacy., Methods: We analysed standard-19 channel-EEG from 25 People with Epilepsy (PwE) both before (T0) and after (T1) the introduction of PER as add-on treatment. Normal values were obtained in 30 healthy controls (HC) matched for sex and age. EEGs were analysed using Matlab™ and the EEGlab and Brainstorm toolkits. We extracted spectral power and connectivity (Phase locking Value) of EEG signal and then compared these features between T0 and T1 and across groups (PwE, HC), we also evaluated the correlations with clinical features., Results: PwE showed increased theta power (p = 0.036) after the introduction of PER but no significant change of EEG connectivity. We also found that PwE have reduced beta power (p = 0.012) and increased connectivity in delta (p = 0.013) and theta (p = 0.007) range as compared to HC, but no significant change was observed between T0 and T1 in PwE. Finally, we found that PwE classified as drug responders to PER have greater alpha power both at T0 and at T1 (p = 0.024) suggesting that this parameter may predict response to treatment., Conclusions: PER causes slight increase of theta activity and does not alter connectivity as assessed by standard EEG. Moreover, greater alpha power could be a good marker of response to PER therapy, and potentially ASM therapy in general., Significance: Our results corroborate the hypothesis that pharmaco-EEG is a viable tool to study neurophysiological changes induced by ASM. Additionally, our work highlights the role of alpha power as a marker of ASM therapeutic response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)