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• This meta-analysis focused on the effectiveness and safety of perampanel for pediatric patients with at least 1-year follow-up in real-world settings. • Twenty-five records involving a total of 2985 individuals were included in the meta-analysis. Nineteen of the studies were followed for one year and six were followed for at least two years. • Perampanel is generally well tolerated and effective in the treatment of epilepsy in children and adolescents with at least 1-year follow-up. • Adverse events, particularly psychiatric and behavioral, should be monitored during clinical practice administration. 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. 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). 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 (I2 = 93 %, P < 0.01, τ2 = 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). 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. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs. Methods: We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs. Results: 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged. Conclusions: CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy. [ABSTRACT FROM AUTHOR]

Although perampanel (PER) has received approval as an antiseizure medication, reports quantifying its antiseizure effects using electroencephalography (EEG) remain scarce. In a previous study, we demonstrated that the interictal high gamma oscillation regularity (GOR) on scalp EEG is an excellent marker of epileptogenicity. Herein, we investigated whether the antiseizure effect of PER could be quantified through interictal GOR analysis of scalp EEG data. To investigate this, we examined the interictal GOR from 20 s of scalp EEG data before and after PER administration collected from five patients with epilepsy with focal seizures. Prior to PER administration, each patient presented with localized areas with high GOR consistent with brain lesions or seizure semiology. In all patients, the seizures improved following PER administration, and the localized high GOR, which is considered an epileptogenic focus, disappeared. These results indicate that interictal GOR analysis may be a useful tool for the quantitative assessments of the antiseizure effects of PER in focal epilepsy. Plain Language Summary: This study explored whether perampanel (PER)'s antiseizure effects can be quantified using interictal high gamma oscillation regularity (GOR) analysis from scalp EEG data. Analyzing 20‐second EEG segments before and after PER administration in five patients with focal epilepsy, we found that high GOR areas, indicative of epileptogenic foci, disappeared following PER administration. The results suggest that interictal GOR analysis could effectively quantify the antiseizure effects of PER. [ABSTRACT FROM AUTHOR]

Objective: To examine the efficacy and safety of perampanel (PER) in patients with post‐stroke epilepsy (PSE), brain tumor‐related epilepsy (BTRE), and post‐traumatic epilepsy (PTE) using Japanese real‐world data. Methods: The prospective post‐marketing observational study included patients with focal seizures with or without focal to bilateral tonic–clonic seizures who received PER combination therapy. The observation period was 24 or 52 weeks after the initial PER administration. The safety and efficacy analysis included 3716 and 3272 patients, respectively. This post hoc analysis examined responder rate (50% reduction in seizure frequency), seizure‐free rate (proportion of patients who achieved seizure‐free), and safety in patients included in the post‐marketing study who had PSE, BTRE, and PTE in the 4 weeks prior to the last observation. Results: Overall, 402, 272, and 186 patients were included in the PSE, BTRE, and PTE subpopulations, and 2867 controls in the "Other" population (etiologies other than PSE, BTRE, or PTE). Mean modal dose (the most frequently administered dose) values at 52 weeks were 3.38, 3.36, 3.64, and 4.04 mg/day for PSE, BTRE, PTE, and "Other," respectively; PER retention rates were 56.2%, 54.0%, 52.6%, and 59.7%, respectively. Responder rates (% [95% confidence interval]) were 82% (76.3%–86.5%), 78% (70.8%–83.7%), 67% (56.8%–75.6%), and 50% (47.9%–52.7%) for PSE, BTRE, PTE, and "Other," respectively, and seizure‐free rates were 71% (64.5%–76.5%), 62% (54.1%–69.0%), 50% (40.6%–60.4%), and 28% (25.8%–30.1%), respectively. Adverse drug reactions tended to occur less frequently in the PSE (14.7%), BTRE (16.5%), and PTE (16.7%) subpopulations than in the "Other" population (26.3%). Significance: In real‐world clinical conditions, efficacy and tolerability for PER combination therapy were observed at low PER doses for the PSE, BTRE, and PTE subpopulations. Plain Language Summary: To find out how well the medication perampanel works and whether it is safe for people who have epilepsy after having had a stroke, brain tumor, or head injury, we used information from real‐life medical situations in Japan. We looked at the data of about 3700 Japanese patients with epilepsy who were treated with perampanel. We found that perampanel was used at lower doses and better at controlling seizures, and had fewer side effects for patients with epilepsy caused by these etiologies than the control group. [ABSTRACT FROM AUTHOR]

Background: Epilepsy is a chronic neurological condition requiring effective management with minimal adverse effects. Lacosamide (LCM) and Perampanel (PER), two promising treatments, have distinct profiles that merit comparative analysis to guide clinical decision-making. Methods: This study utilizes a pharmacovigilance analysis of adverse events reported in the FDA Adverse Event Reporting System database from Q1 2009 to Q3 2023. Employing disproportionality and Bayesian analyses, we assessed and compared the AE signals associated with LCM and PER to elucidate their safety profiles in epilepsy treatment. Results: The analysis included 12,576 AE reports for LCM and 2,703 for PER, highlighting a higher incidence of psychiatric disorders, including aggression with LCM, and a notable association of PER with psychiatric disorders such as psychotic disorders and dizziness. LCM showed a relatively safe profile during pregnancy, whereas PER's data suggested caution due to reported cases of suicidal ideation and attempts. Conclusion: This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of LCM and PER in clinical practice, providing valuable insights for personalized epilepsy management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events. [ABSTRACT FROM AUTHOR]

Background: Post-stroke epilepsy can reduce patients' abilities to carry out various activities of daily living. Despite their importance in preventing the onset of post-stroke epilepsy, the prophylactic administration of antiepileptic drugs is controversial due to a lack of high-level clinical research. In this study, we initiated a prospective interventional study of prophylactic antiepileptic drug administration in patients with a subcortical hemorrhage, who are at the highest risk of developing epilepsy after experiencing a stroke. Methods: The study was conducted in a single-center setting and was a single-arm study with no control group; the case entry period started in November 2023 and is due to end in March 2025. Only cases with a subcortical hemorrhage will be included. The treatment regimen used in this study is 2 mg of perampanel per day. Perampanel will be administered for one year, followed by two years of follow-up, for a total study period of three years. The primary endpoint will be the development of epilepsy. Results: Perampanel administration is expected to reduce the incidence of post-stroke epilepsy in comparison to the results of previous reports on the use of alternative treatments. Conclusions: The results of this study will provide new insights into the prevention of post-stroke epilepsy. The relatively small size of this study makes it difficult to provide strong evidence of the efficacy of perampanel, but it may serve as a basis for larger clinical trials. [ABSTRACT FROM AUTHOR]

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Background: The goal of this study was to develop and validate a UPLC-MS/MS method for simultaneous measurement of 13 AEDs, including carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, topiramate, primidone, zonisamide, gabapentin, lacosamide, perampanel, pregabalin, rufinamide, and vigabatrin, in whole blood samples. Methods: A UPLC-MS/MS method for simultaneous determination of 13 AEDs in whole blood was developed, and validation was conducted for accuracy, precision, limit of quantification (LOQ), matrix effect, and stability. Our method was compared to two different hospitals using UPLC-MS/MS. Results: All AEDs exhibited linearity across the AMR (analytical measurement range), with R² values ranging from 0.994 to 1.000. The imprecision and inaccuracy for low and high quality control (QC) levels were within an acceptable range, with the coefficient of variation (CV) < 15%. The LOQ was 0.62 μg/mL for carbamazepine, 1.61 μg/mL for oxcarbazepine, 1.30 μg/mL for lamotrigine, 13.20 μg/mL for levetiracetam, 1.26 μg/mL for topiramate, 1.01 μg/mL for primidone, 1.59 μg/mL for zonisamide, 1.09 μg/mL for lacosamide, 1.61 μg/mL for gabapentin, 0.50 μg/mL for pregabalin, 0.07 ng/mL for perampanel, 3.00 μg/mL for rufinamide, and 2.06 μg/mL for vigabatrin. All AEDs demonstrated acceptable assay parameters for carryover, stability, and matrix effects. Moreover, the assay showed satisfactory results compared to two different hospitals with a bias of less than 15%. Conclusions: We successfully developed and validated a fast and robust UPLC-MS/MS method for routine therapeutic drug monitoring of thirteen antiepileptic drugs simultaneously. [ABSTRACT FROM AUTHOR]

Abstract Objective To examine the efficacy and safety of perampanel (PER) in patients with post‐stroke epilepsy (PSE), brain tumor‐related epilepsy (BTRE), and post‐traumatic epilepsy (PTE) using Japanese real‐world data. Methods The prospective post‐marketing observational study included patients with focal seizures with or without focal to bilateral tonic–clonic seizures who received PER combination therapy. The observation period was 24 or 52 weeks after the initial PER administration. The safety and efficacy analysis included 3716 and 3272 patients, respectively. This post hoc analysis examined responder rate (50% reduction in seizure frequency), seizure‐free rate (proportion of patients who achieved seizure‐free), and safety in patients included in the post‐marketing study who had PSE, BTRE, and PTE in the 4 weeks prior to the last observation. Results Overall, 402, 272, and 186 patients were included in the PSE, BTRE, and PTE subpopulations, and 2867 controls in the “Other” population (etiologies other than PSE, BTRE, or PTE). Mean modal dose (the most frequently administered dose) values at 52 weeks were 3.38, 3.36, 3.64, and 4.04 mg/day for PSE, BTRE, PTE, and “Other,” respectively; PER retention rates were 56.2%, 54.0%, 52.6%, and 59.7%, respectively. Responder rates (% [95% confidence interval]) were 82% (76.3%–86.5%), 78% (70.8%–83.7%), 67% (56.8%–75.6%), and 50% (47.9%–52.7%) for PSE, BTRE, PTE, and “Other,” respectively, and seizure‐free rates were 71% (64.5%–76.5%), 62% (54.1%–69.0%), 50% (40.6%–60.4%), and 28% (25.8%–30.1%), respectively. Adverse drug reactions tended to occur less frequently in the PSE (14.7%), BTRE (16.5%), and PTE (16.7%) subpopulations than in the “Other” population (26.3%). Significance In real‐world clinical conditions, efficacy and tolerability for PER combination therapy were observed at low PER doses for the PSE, BTRE, and PTE subpopulations. Plain Language Summary To find out how well the medication perampanel works and whether it is safe for people who have epilepsy after having had a stroke, brain tumor, or head injury, we used information from real‐life medical situations in Japan. We looked at the data of about 3700 Japanese patients with epilepsy who were treated with perampanel. We found that perampanel was used at lower doses and better at controlling seizures, and had fewer side effects for patients with epilepsy caused by these etiologies than the control group.

Abstract Although perampanel (PER) has received approval as an antiseizure medication, reports quantifying its antiseizure effects using electroencephalography (EEG) remain scarce. In a previous study, we demonstrated that the interictal high gamma oscillation regularity (GOR) on scalp EEG is an excellent marker of epileptogenicity. Herein, we investigated whether the antiseizure effect of PER could be quantified through interictal GOR analysis of scalp EEG data. To investigate this, we examined the interictal GOR from 20 s of scalp EEG data before and after PER administration collected from five patients with epilepsy with focal seizures. Prior to PER administration, each patient presented with localized areas with high GOR consistent with brain lesions or seizure semiology. In all patients, the seizures improved following PER administration, and the localized high GOR, which is considered an epileptogenic focus, disappeared. These results indicate that interictal GOR analysis may be a useful tool for the quantitative assessments of the antiseizure effects of PER in focal epilepsy. Plain Language Summary This study explored whether perampanel (PER)'s antiseizure effects can be quantified using interictal high gamma oscillation regularity (GOR) analysis from scalp EEG data. Analyzing 20‐second EEG segments before and after PER administration in five patients with focal epilepsy, we found that high GOR areas, indicative of epileptogenic foci, disappeared following PER administration. The results suggest that interictal GOR analysis could effectively quantify the antiseizure effects of PER.

Background Currently, the treatment of refractory epilepsy (RE) in children is still a difficult point in epilepsy treatment. In China, pirenzapine (PER) is still a new drug for treating RE in children, and there is currently a lack of recommendations for adding PER to the treatment of RE in children. And in Chinese reports, the sample size of RE patients treated with PER is relatively small. Therefore, the efficacy of PER for pediatric RE, especially for young children with RE, still needs to be further studied with a large sample size. Objective To explore the efficacy, possible indications, adverse reactions, and tolerability of PER addition therapy for RE in children. Methods A self-control and retrospective analysis was conducted on children with RE aged 0-18 who were treated at the Women and Children's Hospital, Qingdao University from January 2022 to January 2023. The frequency of seizures at different observation points before and after the addition of PER treatment was compared, and the effective rate of PER was evaluated. Adverse drug reactions and drug retention rates were recorded, and the clinical characteristics of the effective and ineffective groups of PER were analyzed. Results A total of 192 study subjects were included. After adding PER treatment, the effective rates at 12, 24, and 36 weeks were 56.3% (108/192), 62.1% (113/182), and 69.7% (122/175), respectively, and the seizure free rates were 19.3% (37/192), 21.4% (39/182), and 24.6% (43/175). The incidence of adverse reactions was 16.1% (31/192), mainly including dizziness, irritability, weakness, and drowsiness. The last follow-up drug retention rate was 91.1% (175/192). There was a statistically significant difference in the onset age, duration of anti-epileptic treatment, type of origin, seizure form, frequency of seizures before the addition of PER, number of combined anti-epileptic drugs (ASMs), and ketogenic diet/surgical treatment between patients with RE who received continuous medication for 12 weeks (P

Objective: Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, has been approved as adjunctive therapy for focal and generalized epilepsy. Limited information is available regarding the measurable impact of anti-seizure medications (ASM). In this study, we aimed to investigate the effects of PER on electroencephalography (EEG) background activity and interictal epileptic discharge. Methods: This study included all patients with a clinical diagnosis of epilepsy who underwent routine EEG before and after PER treatment between 2018 and 2023. EEG findings were examined according to their background activity and clinical features such as risk factors of epilepsy, the occurrence of sleep-related seizures, sleep disorders, intellectual disability, abnormality of magnetic resonance imaging and EEG, multifocal features on EEG, the duration between EEG and initiation of PER treatment, frequency of seizures before and after PER treatment (seizure freedom or >50% reduction in seizures), previous epilepsy surgery, the number of current and previous ASM, and dosage of PER. Results: In a total of 11 patients, epilepsy type was focal in 8 (73%), all of the patients were on polytherapy, and 4 of them had undergone epilepsy surgery. PER treatment resulted in seizure freedom in 36% of patients and a >50% decrease in seizures in 55% of patients. There was no statistically significant relationship between background activity, phase reversal, and equipotential in EEG before and after PER treatment. In addition, pre- and posttreatment responses to activation procedures and disruption in sleep structure did not differ significantly. The relationship between seizure freedom and phase reversal decrease after PER treatment was statistically significant. The relationship between a >50% decrease in the frequency of seizures and epileptic discharges also reached statistical significance. Conclusion: To summarize, seizure freedom following PER treatment appears to be associated with reduced epileptic discharge, and EEG monitoring might help determine prognosis.

Objective: Perampanel (PER), a noncompetitive a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, has been approved as adjunctive therapy for focal and generalized epilepsy. Limited information is available regarding the measurable impact of anti-seizure medications (ASM). In this study, we aimed to investigate the effects of PER on electroencephalography (EEG) background activity and interictal epileptic discharge. Methods: This study included all patients with a clinical diagnosis of epilepsy who underwent routine EEG before and after PER treatment between 2018 and 2023. EEG findings were examined according to their background activity and clinical features such as risk factors of epilepsy, the occurrence of sleep-related seizures, sleep disorders, intellectual disability, abnormality of magnetic resonance imaging and EEG, multifocal features on EEG, the duration between EEG and initiation of PER treatment, frequency of seizures before and after PER treatment (seizure freedom or >50% reduction in seizures), previous epilepsy surgery, the number of current and previous ASM, and dosage of PER. Results: In a total of 11 patients, epilepsy type was focal in 8 (73%), all of the patients were on polytherapy, and 4 of them had undergone epilepsy surgery. PER treatment resulted in seizure freedom in 36% of patients and a >50% decrease in seizures in 55% of patients. There was no statistically significant relationship between background activity, phase reversal, and equipotential in EEG before and after PER treatment. In addition, pre- and posttreatment responses to activation procedures and disruption in sleep structure did not differ significantly. The relationship between seizure freedom and phase reversal decrease after PER treatment was statistically significant. The relationship between a >50% decrease in the frequency of seizures and epileptic discharges also reached statistical significance. Conclusion: To summarize, seizure freedom following PER treatment appears to be associated with reduced epileptic discharge, and EEG monitoring might help determine prognosis. [ABSTRACT FROM AUTHOR]

Abstract Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post‐dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. Plain Language summary Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.

Sleep disorders occur twice as often in epilepsy patients compared to healthy people and have a negative impact on seizure control and general quality of life. International and Russian publications on the effect of perampanel (PER) on sleep emphasise the positive effect of the drug on sleep quality, daytime sleepiness and sleep architecture.Objective: to evaluate the effect of PER (Fycompa®) on sleep quality and daytime sleepiness when used as an adjunct antiepileptic drug (AED) in the treatment of epilepsy in adults.Material and methods. The study included 106 patients aged 18 to 73 years with absolute predominance of focal epilepsy (n=96) who were prescribed PER as an adjunctive AED when previous therapy was insufficient, regardless of whether or not complaints of insomnia were present. The study was conducted from April 2022 to June 2023. The maximum observation period was 12 months. The study was multicenter (10 Russian clinical centres) and designed as an observational study, with patients being monitored prospectively, but some of the indicators were collected retrospectively, taking into account the conditions of real-life clinical practice. We assessed: sleep quality using the Pittsburgh Insomnia Scale (Ya.I. Levin modification), daytime sleepiness according to the Epworth scale, anxiety/depression level (Hospital Anxiety and Depression Scale, HADS), adverse events (AEs), efficacy/tolerability of combination therapy with PER for epilepsy at baseline, and after 1, 3, 6 and 12 months of therapy based on the number of completed questionnaires at each visit in the real-life clinical practice.Results. After a follow-up period of 12 months, the retention rate for complex therapy with PER was 84.9%. PER was discontinued in 15.1% of patients and in only 5.7% due to AEs. The most common AE was dizziness, which was observed with a frequency of over 10% (n=21), followed by irritability (n=9) and drowsiness (n=9) with the same frequency. No new, previously undescribed AEs were observed in this study. The use of PER as an additional AED led to a significant reduction in daytime sleepiness and an improvement in sleep quality after the first month of use; by the 12-month follow-up period, the daytime sleepiness index gradually decreased and reached normal levels, and sleep quality improved. The use of PER as part of a complex therapy led to a significant reduction in the initially elevated anxiety level.Conclusion. The use of PER as an additional AED in adults in dynamics significantly improves sleep quality and reduces daytime sleepiness after the first month of use, regardless of the duration of the disease and the order of PER administration. The use of PER as part of a complex therapy led to a decrease in the initially elevated anxiety level from subclinical to normal.

Abstract Objective To report the interim results of the PERPRISE study (Study 509; NCT04202159), which is evaluating perampanel as the only adjunctive anti‐seizure medication (ASM) in adults with focal to bilateral tonic–clonic seizures (FBTCS) or primary generalized tonic–clonic seizures (GTCS). Methods PERPRISE is an ongoing 12‐month multicenter, prospective, observational, non‐interventional study of perampanel in a real‐world setting in Germany. Patients are aged ≥18 years with FBTCS or GTCS due to focal or idiopathic generalized epilepsy. Perampanel, as an adjunctive therapy to ASM monotherapy (‘add‐on therapy’) or as a substitute for one ASM in dual therapy (‘substitution therapy’), is prescribed in line with its SmPC. The Interim Analysis Set comprises the first 100 patients who received ≥1 dose of perampanel and attended or discontinued prior to the ~6‐month visit. Interim endpoints include retention rate, measures of effects on seizure frequency, and treatment‐emergent adverse events (TEAEs). Results One hundred patients were included in the Interim Analysis Set (add‐on, n = 43 [43.0%]; substitution, n = 55 [55.0%]; unknown, n = 2). The 6‐month retention rate was 78.0% (add‐on, 83.7%; substitution, 72.7%). For the overall population with GTCS and/or FBTCS, seizure‐freedom rate at 6 months was 58.8% (add‐on, 72.2%; substitution, 47.9%) and 50% responder rate at 6 months was 82.6% (add‐on, 89.2%; substitution, 76.6%). Retention rates and seizure outcomes were better with perampanel as an early‐line treatment than as a late‐line treatment. TEAEs were reported by 48 patients (48.0%), most commonly dizziness (n = 9), fatigue (n = 7), and irritability (n = 7). Sixteen patients (16.0%) withdrew from perampanel treatment due to TEAEs. Significance The interim analysis of PERPRISE offers insight into the real‐world use of perampanel in Germany, including for the first time, clinical practice data from patients with GTCS and switching ASMs within a dual therapy. Further data from PERPRISE will be of value to inform clinical decision‐making in this patient cohort. Plain Language Summary Patients with epilepsy often take more than one medication for seizure control. This 12month study looked at patients in Germany receiving perampanel as only add‐on medication. The interim analysis shows, that at 6 months, over 70% of the 100 patients continued to use perampanel; 59% experienced no seizures during treatment with perampanel, and in 83%, seizure frequency was reduced by half. Side effects occurred in 48% of patients (most commonly dizziness, fatigue, and irritability) and caused 16% to withdraw from the study. Overall, perampanel was a suitable as only add‐on medication for patients with epilepsy.

Abstract Objective ESPRITE (Study 508; NCT03836924) evaluated the real‐world safety, tolerability, and efficacy of adjunctive perampanel in patients aged ≥12 years with focal‐onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS), in India. Methods ESPRITE was a prospective, multicenter, single‐arm, observational, Phase IV study with a 6‐month Treatment Period. Patients were aged ≥12 years and had been prescribed perampanel for adjunctive treatment of FOS, with or without FBTCS. Assessments included incidence of treatment‐emergent adverse events (TEAEs; primary endpoint), median percent reduction in seizure frequency per 28 days from baseline, 50% responder rates, and seizure‐freedom rates. Results Overall, 200 patients were enrolled (199 patients in the Safety Analysis Set and 174 patients who completed all visits in the main efficacy analyses). TEAEs (all mild or moderate in severity) were reported in 18.1% (n = 36/199) of patients (the most common were dizziness [3.0%] and irritability [2.0%]). TEAEs leading to discontinuation of perampanel were reported in 2.0% of patients; no deaths or serious TEAEs occurred. At 6 months, median percent reduction in seizure frequency was 100.0%, 50% responder rate was 83.3%, and seizure‐freedom rate was 49.4%. Significance Adjunctive perampanel (at a mean daily dose of 4 mg/day) was shown to be well tolerated and effective in patients aged ≥12 years with FOS, with or without FBTCS, from India. Plain Language Summary Many patients do not receive adequate treatment for epilepsy and need effective seizure control medications. In this 6‐month clinical study, 199 patients from India, aged 12 years or older, added perampanel to the anti‐seizure medications they were already taking. At 6 months, 49% of patients experienced no seizures since starting perampanel and seizure frequency was reduced by half in 83% of patients. Side effects occurred in 18% of patients (most commonly dizziness and irritability) and caused 2% to stop perampanel; no deaths were reported. Perampanel was an effective and generally safe added medication for patients with epilepsy from India.

• In the time–frequency analysis, P25 and N35 showed power increases of high-frequency activities in comparison to baseline activities, while P50 showed a power decrease. • Short-latency of giant SEPs (P25 and N35) reflect evoked paroxysmal depolarization shifts. • Middle latency of giant SEPs (P50) reflects the inhibitory component. 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. 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. 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. 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. MLCs of giant SEPs reflected inhibitory components. [ABSTRACT FROM AUTHOR]

Objective: Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T‐PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T‐PSC design also could replicate the trial's safety and tolerability conclusions. Methods: We retrospectively applied the T‐PSC design to analyze treatment‐emergent adverse events (TEAEs) from a blinded, placebo‐controlled trial of perampanel for primary generalized tonic–clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment‐related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T‐PSC relative to those observed during the full‐length trial. Results: Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full‐length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T‐PSC, respectively. When limited to treatment‐related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment‐related TEAEs that occurred before T‐PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T‐PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p =.035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T‐PSC, one in placebo and two in perampanel). Significance: Almost all TEAEs occurred before T‐PSC. More treatment‐related TEAEs occurred after T‐PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T‐PSC or delayed time to TEAE for placebo. [ABSTRACT FROM AUTHOR]

• Plasma concentration of perampanel was affected by genetic polymorphisms of cytochrome P450 (CYP)3A4 gene. • The CYP3A4×10 GC group showed the highest plasma concentration of PER compared to CC phenotype groups (p < 0.05). • The proportion of patients with adverse events was the highest in the CYP3A4×10 TT and CYP3A4×10 GC group (77.8% vs. 77.8 %). • The PER plasma concentration had a significant relationship between exposure (p < 0.05) or toxicity (p < 0.05). 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post‐dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. Plain Language summary: Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications. [ABSTRACT FROM AUTHOR]

Objective: In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal‐onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real‐world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult‐to‐treat epilepsies. Our aim was to investigate the efficacy of add‐on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add‐on lacosamide, perampanel, and brivaracetam therapy. Methods: Patients were enrolled from the CENKORK study, which is a prospective, non‐interventional, open‐label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure‐free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. Results: Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow‐up, leaving 150 cases for the 1‐year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6‐month and 1‐year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6‐month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). Significance: Add‐on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. Plain Language Summary: This observational study was carried out in 172 adult patients with difficult‐to‐treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy and safety of perampanel (PER) as an adjunctive therapy in children aged 4–12 years with epilepsy. Methods: We performed a non-randomized, open-label, placebo-uncontrolled, real-world self-controlled study that included 216 young children (aged 4–12 years) with epilepsy who received PER as adjunctive therapy at the children's hospital affiliated with Chongqing Medical University from July 4, 2020, to September 20, 2023. Results: (1) The efficacy rates of adjunctive PER therapy at 3, 6, 9, and 12 months were 62.8%, 67.8%, 65.3%, and 61.2%, respectively. PER showed efficacy in alleviating focal seizures, generalized tonic–clonic seizures, myoclonic seizures, and absence seizures. The efficacy rates for variants of self-limited epilepsy with centrotemporal spikes (SeLECTS) and Lennox-Gastaut syndrome (LGS) were 89.5% and 66.7%, respectively. (2) Focal non-motor onset seizures with or without impaired awareness, focal to bilateral tonic–clonic seizures (FBTCS), LGS, variants of SeLECTS, the number of concomitant antiseizure medications (ASMs), a family history of epilepsy, and focal lesions on cranial magnetic resonance imaging were independent factors affecting efficacy. The order of PER addition did not affect efficacy. The retention rates at 3, 6, 9, and 12 months were 90.7%, 84.7%, 74.7%, 64.9%, respectively. (3) Adverse reactions occurred in 45 patients (45/216, 20.8%), with irritability/aggressive behavior (18/216, 8.3%) and somnolence (14/216, 6.5%) being the most common. Twelve patients (12/216, 5.6%) withdrew from the study because of adverse reactions. Conclusion: In young Chinese children with epilepsy, PER is effective, safe, and well-tolerated as an adjunctive therapy, making it a viable option for use with broad-spectrum ASMs. [ABSTRACT FROM AUTHOR]

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4 years with focal-onset seizures or generalized tonic–clonic seizures in the United States. The study included Screening, Titration (≤ 13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, perampanel was initiated at 2 mg/day and up-titrated to 4 mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12 mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8 weeks and 32 (59.3%) patients completed the study. Retention rate at 12 months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy. [ABSTRACT FROM AUTHOR]

Perampanel (PER) is a new type of antiseizure medication used for partial or generalized seizures. However, the plasma concentration shows obvious individual variability in children. The present study aims to ascertain the effect of age, comedications, and cytochrome P450 (CYP) 3A4/5 polymorphisms on PER exposure in Chinese pediatric patients with epilepsy. Clinical data were retrospectively collected in a tertiary children's hospital medical records system from January 2021 to December 2022. The influence factors on the daily dose, plasma concentration, and concentration‐to‐dose ratio (CDR) of PER were investigated. A total of 135 pediatric patients with 178 blood samples were involved. With a median daily dose of 4.0 mg (interquartile range, 3.0‐5.0 mg), the median plasma concentration was 409.4 ng/mL (interquartile range, 251.7‐639.4 ng/mL). The CDR in patients aged less than 4 years was significantly decreased by 48.0% and 39.1% compared with those aged 4‐11 years and 12 years or older, respectively. Enzyme inducers significantly decreased the CDR of PER by 34.5%, while valproic acid showed an increase of 71.7%. In addition, genotype CYP3A5*3/*3 carriers presented a significant increase of 21.5% compared to the CYP3A5*1/*3 expresser. No correlations were observed between the CDR and CYP3A4∗1G polymorphism. PER showed high variations in individual plasma concentrations. Age younger than 4 years, comedication with enzyme inducers or valproic acid, and possession of the CYP3A5*3 genotype potentially predicted PER exposure in pediatric patients with epilepsy. [ABSTRACT FROM AUTHOR]

Objective: The purposes of this study were to explore the pharmacokinetics of perampanel (PER) in children with epilepsy, identify factors that contribute to pharmacokinetic variations among subjects, evaluate the connection between PER exposure and clinical outcome, and establish an evidence‐based approach for tailoring individualized antiepileptic treatment in this specific population. Methods: In this prospective study, PER plasma concentrations and genetic information on metabolic enzymes were obtained from 194 patients younger than 18 years. The disposition kinetics of PER in pediatric patients following oral dosing were characterized using nonlinear mixed effect models. The effective range for the plasma concentration of PER was determined by assessing the efficacy and safety of PER treatment and analyzing the relationship between drug exposure and clinical response. Monte Carlo simulations were then performed to evaluate and optimize the current dosing regimens. Results: The pharmacokinetic profile of PER was adequately described by a one‐compartment model with first‐order absorption and elimination. Body weight, total bilirubin level, and concomitant oxcarbazepine were found to have significant influences on PER pharmacokinetics. Model estimates of apparent clearance and volume of distribution were.016 ±.009 L/h/kg and 1.47 ±.78 L/kg, respectively. The effective range predicted from plasma concentration data in responders was 215–862 μg/L. Dosing scenarios stratified according to essential covariates were proposed through simulation analysis. Significance: In this study, we captured the pharmacokinetic/pharmacodynamic characteristics of PER in pediatric epilepsy patients through analysis of real‐world data and adopted a pharmacometric approach to support an individualized dosing strategy for PER in this specific population. [ABSTRACT FROM AUTHOR]

Introduction: It is important to assess the effectiveness of an antiseizure medication in treating different epilepsy aetiologies to optimise individualised therapeutic approaches. Data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study were used to assess the effectiveness and safety/tolerability of perampanel (PER) when used to treat individuals with a range of epilepsy aetiologies in clinical practice. Methods: A post hoc analysis was conducted of PERMIT Extension data from individuals with a known aetiology. Retention was assessed after 3, 6 and 12 months. Effectiveness was assessed after 3, 6 and 12 months and at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥ 50% seizure frequency reduction) and seizure freedom rate (no seizures since at least the prior visit). Safety/tolerability was assessed by evaluating adverse events (AEs) and AEs leading to discontinuation. Results: PERMIT Extension included 1945 individuals with structural aetiology, 1012 with genetic aetiology, 93 with an infectious aetiology, and 26 with an immune aetiology. Retention rates at 12 months were 61.1% (structural), 65.9% (genetic), 56.8% (infectious) and 56.5% (immune). At the last visit, responder rates (total seizures) were 43.3% (structural), 68.3% (genetic), 37.0% (infectious) and 20.0% (immune), and corresponding seizure freedom rates were 15.8%, 46.5%, 11.1% and 5.0%, respectively. AE incidence rates were 58.0% (structural), 46.5% (genetic), 51.1% (infectious) and 65.0% (immune), and corresponding rates of discontinuation due to AEs over 12 months were 18.9%, 16.4%, 18.5% and 21.7%, respectively. The types of AEs reported were generally consistent across aetiology subgroups, with no idiosyncratic AEs emerging. Conclusion: Although PER was effective and generally well tolerated when used to treat individuals with a range of epilepsy aetiologies in clinical practice, variability in its effectiveness and tolerability across the subgroups indicates that PER may be particularly useful for individuals with specific epilepsy aetiologies. [ABSTRACT FROM AUTHOR]

Objective: ESPRITE (Study 508; NCT03836924) evaluated the real‐world safety, tolerability, and efficacy of adjunctive perampanel in patients aged ≥12 years with focal‐onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS), in India. Methods: ESPRITE was a prospective, multicenter, single‐arm, observational, Phase IV study with a 6‐month Treatment Period. Patients were aged ≥12 years and had been prescribed perampanel for adjunctive treatment of FOS, with or without FBTCS. Assessments included incidence of treatment‐emergent adverse events (TEAEs; primary endpoint), median percent reduction in seizure frequency per 28 days from baseline, 50% responder rates, and seizure‐freedom rates. Results: Overall, 200 patients were enrolled (199 patients in the Safety Analysis Set and 174 patients who completed all visits in the main efficacy analyses). TEAEs (all mild or moderate in severity) were reported in 18.1% (n = 36/199) of patients (the most common were dizziness [3.0%] and irritability [2.0%]). TEAEs leading to discontinuation of perampanel were reported in 2.0% of patients; no deaths or serious TEAEs occurred. At 6 months, median percent reduction in seizure frequency was 100.0%, 50% responder rate was 83.3%, and seizure‐freedom rate was 49.4%. Significance: Adjunctive perampanel (at a mean daily dose of 4 mg/day) was shown to be well tolerated and effective in patients aged ≥12 years with FOS, with or without FBTCS, from India. Plain Language Summary: Many patients do not receive adequate treatment for epilepsy and need effective seizure control medications. In this 6‐month clinical study, 199 patients from India, aged 12 years or older, added perampanel to the anti‐seizure medications they were already taking. At 6 months, 49% of patients experienced no seizures since starting perampanel and seizure frequency was reduced by half in 83% of patients. Side effects occurred in 18% of patients (most commonly dizziness and irritability) and caused 2% to stop perampanel; no deaths were reported. Perampanel was an effective and generally safe added medication for patients with epilepsy from India. [ABSTRACT FROM AUTHOR]

Objective: To report the interim results of the PERPRISE study (Study 509; NCT04202159), which is evaluating perampanel as the only adjunctive anti‐seizure medication (ASM) in adults with focal to bilateral tonic–clonic seizures (FBTCS) or primary generalized tonic–clonic seizures (GTCS). Methods: PERPRISE is an ongoing 12‐month multicenter, prospective, observational, non‐interventional study of perampanel in a real‐world setting in Germany. Patients are aged ≥18 years with FBTCS or GTCS due to focal or idiopathic generalized epilepsy. Perampanel, as an adjunctive therapy to ASM monotherapy ('add‐on therapy') or as a substitute for one ASM in dual therapy ('substitution therapy'), is prescribed in line with its SmPC. The Interim Analysis Set comprises the first 100 patients who received ≥1 dose of perampanel and attended or discontinued prior to the ~6‐month visit. Interim endpoints include retention rate, measures of effects on seizure frequency, and treatment‐emergent adverse events (TEAEs). Results: One hundred patients were included in the Interim Analysis Set (add‐on, n = 43 [43.0%]; substitution, n = 55 [55.0%]; unknown, n = 2). The 6‐month retention rate was 78.0% (add‐on, 83.7%; substitution, 72.7%). For the overall population with GTCS and/or FBTCS, seizure‐freedom rate at 6 months was 58.8% (add‐on, 72.2%; substitution, 47.9%) and 50% responder rate at 6 months was 82.6% (add‐on, 89.2%; substitution, 76.6%). Retention rates and seizure outcomes were better with perampanel as an early‐line treatment than as a late‐line treatment. TEAEs were reported by 48 patients (48.0%), most commonly dizziness (n = 9), fatigue (n = 7), and irritability (n = 7). Sixteen patients (16.0%) withdrew from perampanel treatment due to TEAEs. Significance: The interim analysis of PERPRISE offers insight into the real‐world use of perampanel in Germany, including for the first time, clinical practice data from patients with GTCS and switching ASMs within a dual therapy. Further data from PERPRISE will be of value to inform clinical decision‐making in this patient cohort. Plain Language Summary: Patients with epilepsy often take more than one medication for seizure control. This 12month study looked at patients in Germany receiving perampanel as only add‐on medication. The interim analysis shows, that at 6 months, over 70% of the 100 patients continued to use perampanel; 59% experienced no seizures during treatment with perampanel, and in 83%, seizure frequency was reduced by half. Side effects occurred in 48% of patients (most commonly dizziness, fatigue, and irritability) and caused 16% to withdraw from the study. Overall, perampanel was a suitable as only add‐on medication for patients with epilepsy. [ABSTRACT FROM AUTHOR]

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.

Value of drug level concentrations of brivaracetam, lacosamide, and perampanel in care of people with epilepsy Hentschel M, Stoffel-Wagner B, Surges R, Surges R, Dolscheid-Pommerich RC. Epilepsia. 2024 Mar;65(3):620–629. doi:10.1111/epi.17873. Epub 2024 Jan 19 Objective: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range have led to dose adjustments. Methods: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography-tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. The clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of the current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration. Results: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, P = 1.000; LCM, P =.243; PER, P =.113) or responder status (BRV, P =.118; LCM, P =.478; PER, P =.069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%). Significance: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Abstract Objective To evaluate the long‐term efficacy, safety, and tolerability of adjunctive perampanel for the treatment of patients with refractory focal‐onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS), from the Asia‐Pacific region. Methods Study 335 (NCT01618695) was a randomized, double‐blind, placebo‐controlled, Phase III study. Patients aged ≥12 years with refractory FOS who completed the Core Study could enter an open‐label extension (OLEx) Phase (6‐week Conversion and ≥46‐week Maintenance Period). Endpoints included median percent reduction in seizure frequency per 28 days, 50% responder and seizure‐freedom rates, and treatment‐emergent adverse events (TEAEs). Results The Intent‐to‐Treat Analysis Set included 704 patients (529 received perampanel and 175 received placebo during the Core Study; all patients received perampanel during OLEx). The median percent reduction in seizure frequency and 50% responder rates in patients who received perampanel during the Core Study were maintained throughout the OLEx Phase (Week 64–75: 55.9% and 54.3%, respectively). Seizure freedom for ≥12 consecutive months at any time during perampanel treatment was achieved by 4.1% of patients with FOS and 14.2% of patients with FBTCS. Among patients treated with perampanel 4 mg/day (n = 83), median reduction in seizure frequency was lower in those who received concomitant enzyme‐inducing anti‐seizure medications (EIASMs) than those who received non‐EIASMs. The most common TEAE was dizziness (n = 318; 46.8%); 141 (20.8%) patients had TEAEs that led to study/drug withdrawal. Significance Overall, long‐term seizure control was achieved with adjunctive perampanel in patients with refractory FOS, with or without FBTCS, in an Asia‐Pacific population.

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.

BACKGROUND: There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review. METHODS: We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents. RESULTS: Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties. DISCUSSION: Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication.

An abnormal glutamate signaling of glioblastoma may contribute to both tumor progression and the generation of glioma-associated epileptic seizures. We hypothesized that the AMPA receptor antagonist perampanel (PER) could attenuate tumor growth and epileptic events. F98 glioma cells, grown orthotopically in Fischer rats, were employed as a model of glioma to investigate the therapeutic efficiency of PER (15 mg/kg) as adjuvant to standard radiochemotherapy (RCT). The epileptiform phenotype was investigated by video-EEG analysis and field potential recordings. Effects on glioma progression were estimated by tumor size quantification, survival analysis and immunohistological staining. Our data revealed that orthotopically-growing F98 glioma promote an epileptiform phenotype in rats. RCT reduced the tumor size and prolonged the survival of the animals. The adjuvant administration of PER had no effect on tumor progression. The tumor-associated epileptic events were abolished by PER application or RCT respectively, to initial baseline levels. Remarkably, PER preserved the glutamatergic network activity on healthy peritumoral tissue in RCT-treated animals. F98 tumors are not only a robust model to investigate glioma progression, but also a viable model to simulate a glioma-associated epileptiform phenotype. Furthermore, our data indicate that PER acts as a potent anticonvulsant and may protect the tumorsurrounding tissue as adjuvant to RCT, but failed to attenuate tumor growth or promote animal survival. [ABSTRACT FROM AUTHOR]

The non-interventional Phase IV PROVE study (NCT03208660) assessed retention, efficacy, safety and tolerability, and perampanel dosing in patients with epilepsy during routine clinical care. This analysis evaluated final data from patients aged <4 years and 4–<12 years. Data were obtained retrospectively from medical/pharmacy records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinician recommendations. Retention rate was the primary endpoint. Secondary assessments included median percent changes in seizure frequency, seizure-freedom rates, investigator impression of seizure effect, and safety and tolerability. The Safety Analysis Set (SAS) included 41 patients (<4 years; mean maximum dose, 3.5 mg/day) and 203 patients (4–<12 years; mean maximum dose, 5.3 mg/day); 24-month retention rates were 35.7% (n = 5/14) and 42.0% (n = 47/112), respectively. In the Full Analysis Set, during Months 1–3, median percent reductions in seizure frequency were 33.3% (n = 8 [<4 years]) and 26.0% (n = 32 [4–<12 years]), and seizure-freedom rates were 12.5% in both groups (n = 1/8 and n = 4/32); patient numbers were low at later time points. Most patients showed improvements in seizure control (45.9% [<4 years] versus 52.4% [4–<12 years]) or no change (45.9% versus 34.5%) (SAS). Treatment-emergent adverse events (TEAEs) were reported in 12 (<4 years: 29.3%; most common, irritability [7.3%]) and 64 patients (4–<12 years: 31.5%; most common, aggression [6.9%]). Perampanel was generally well tolerated with <21% of TEAEs leading to withdrawal at 24 months, had favorable retention rates (≥50% and >35% at 12 and 24 months, respectively), and sustained efficacy in pediatric patients during routine clinical care. • PROVE was a retrospective Phase IV study of perampanel in patients with epilepsy. • This analysis assessed perampanel efficacy/safety/tolerability in patients aged <12 years. • Perampanel was associated with 36–42% retention rates at 2 years. • The efficacy of perampanel was sustained for up to 2 years in pediatric patients. • TEAEs leading to perampanel withdrawal were reported in <21% of patients at 2 years. [ABSTRACT FROM AUTHOR]

• This study aimed to determine clinical characteristics predicting PER response and assess the role of structural connectivity. • Early PER administration was identified as a predictor of good PER response in patients with epilepsy. • The cortical and subcortical structural connectivity exhibited different network characteristics related to PER response. This study aimed to identify clinical characteristics that could predict the response to perampanel (PER) and determine whether structural connectivity is a predictive factor. 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. 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). 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. [ABSTRACT FROM AUTHOR]

• A multicenter observational study of first add-on perampanel treatment was conducted. • The seizure-free, response, and retention rates were 45.6 %, 74.7 %, and 82.1 %. • The type of concomitant ASMs and etiological classification of epilepsy were related with the efficacy of PER as the first add-on therapy. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Focal epilepsy constitutes the most common epilepsy in children, and medical treatment represents the first-line therapy in this condition. The main goal of medical treatment for children and adolescents with epilepsy is the achievement of seizure freedom or, in drug-resistant epilepsies, a significant seizure reduction, both minimizing antiseizure medications (ASM)-related adverse events, thus improving the patient's quality of life. However, up to 20–40% of pediatric epilepsies are refractory to drug treatments. New ASMs came to light in the pediatric landscape, improving the drug profile compared to that of the preexisting ones. Clinicians should consider several factors during the drug choice process, including patient and medication-specific characteristics. This narrative review aims to summarize the latest evidence on the effectiveness and tolerability of the newest ASMs administered as monotherapy or adjunctive therapy in pediatric epilepsies with focal onset seizures, providing a practical appraisal based on the existing evidence. The latest ASMs have the potential to be effective in the pharmacological management of focal onset seizures in children, and treatment choice should consider several drug- and epilepsy-related factors. Future treatments should be increasingly personalized and targeted on patient-specific pathways. Future research should focus on discovering new chemical compounds and repurposing medications used for other indications. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the long‐term efficacy, safety, and tolerability of adjunctive perampanel for the treatment of patients with refractory focal‐onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS), from the Asia‐Pacific region. Methods: Study 335 (NCT01618695) was a randomized, double‐blind, placebo‐controlled, Phase III study. Patients aged ≥12 years with refractory FOS who completed the Core Study could enter an open‐label extension (OLEx) Phase (6‐week Conversion and ≥46‐week Maintenance Period). Endpoints included median percent reduction in seizure frequency per 28 days, 50% responder and seizure‐freedom rates, and treatment‐emergent adverse events (TEAEs). Results: The Intent‐to‐Treat Analysis Set included 704 patients (529 received perampanel and 175 received placebo during the Core Study; all patients received perampanel during OLEx). The median percent reduction in seizure frequency and 50% responder rates in patients who received perampanel during the Core Study were maintained throughout the OLEx Phase (Week 64–75: 55.9% and 54.3%, respectively). Seizure freedom for ≥12 consecutive months at any time during perampanel treatment was achieved by 4.1% of patients with FOS and 14.2% of patients with FBTCS. Among patients treated with perampanel 4 mg/day (n = 83), median reduction in seizure frequency was lower in those who received concomitant enzyme‐inducing anti‐seizure medications (EIASMs) than those who received non‐EIASMs. The most common TEAE was dizziness (n = 318; 46.8%); 141 (20.8%) patients had TEAEs that led to study/drug withdrawal. Significance: Overall, long‐term seizure control was achieved with adjunctive perampanel in patients with refractory FOS, with or without FBTCS, in an Asia‐Pacific population. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis aimed to assess the effectiveness and safety of novel antiepileptic drugs (AEDs) in treating epilepsy in patients with brain tumors (BTRE). Methods: A search was conducted on PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to February 2023, with English language restriction. Results: In this meta-analysis, 18 clinical trials involving 755 BTRE patients were included to assess the efficacy and safety of novel AEDs in BTRE treatment. At the last follow-up, a =50% reduction in seizure frequency was experienced by 72% of patients (random-effects model, 95% CI = 0.64-0.78) using novel AEDs. At the last follow-up, seizure freedom was experienced by 34% of patients (random-effects model, 95% CI = 0.28-0.41) using novel AEDs. The pooled incidence of AEs was found to be 19% (95% CI: 13%-26%), with a withdrawal rate due to adverse effects of only 3%. Comparable efficacy and incidence of adverse effects were observed between lacosamide and perampanel. Conclusion: This meta-analysis suggests that novel antiepileptic drugs are deemed effective for seizure control in brain tumor patients, particularly when used as adjunctive therapy. Although lacosamide and perampanel received more focus in studies, no significant difference was observed in the efficacy and adverse reactions of these two drugs in seizure control. Further randomized controlled trials are deemed necessary to validate our findings. [ABSTRACT FROM AUTHOR]

Background: There is currently a lack of studies examining the long-term therapeutic effectiveness of the third-generation anti-sezure medication, perampanel (PER), for focal-onset seizures (FOS), particularly in Chinese patients with sleep-related epilepsy (SRE). Additionally, the appropriate dosage, plasma concentration, and the relationship between dose and plasma concentration of PER in Chinese patients are still uncertain. Methods: A prospective, single-center, 24-month observational study was conducted in patients diagnosed with FOS, with a focus on patients with SRE. Changes in seizure frequency from baseline, adverse events, and retention rates were analyzed at 12 and 24 months following the start of the treatment. Tolerability was evaluated based on adverse events and discontinuation profiles. PER plasma concentrations were used to assess dose-concentration-response relationships. Results: A total of 175 patients were included (median age: 25 years; range: 4–72 years; 53. 1% males and 46.9% females), with the SRE population accounting for 49. 1% (n = 86). The patients diagnosed with SRE showed considerably higher response rates than those who did not have this diagnosis (p = 0.025, odds ratio = 3.8). Additionally, the SRE group adhered better to PER treatment (r = 0.0009). Patients with a shorter duration of epilepsy (median: 3 years; range:2–7 years) demonstrated a more favorable therapeutic response to PER (p = 0.032). Throughout the administration of maintenance doses, among the entire FOS population, the concentration of PER (C0) ranged between 101.5 and 917.4 ng/mL (median, 232.0 ng/mL), and the mean plasma concentration of PER in the responders was 292.8 ng/mL. We revealed a linear relationship between PER dose and plasma concentration, regardless of whether PER was used as monotherapy or add-on therapy. The retention rates were 77.7% and 65. 1% at 12 and 24 months, respectively. Drug-related adverse events occurred in 45.0% of the patients and were mostly manageable. Conclusion: PER effectively reduced seizure frequency in Chinese patients with FOS, particularly in those with SRE, over a 24-month period. The treatment was well-tolerated and had a clear linear dose-plasma concentration relationship. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range has led to dose adjustments. Methods: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography–tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. Clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration. Results: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, p = 1.000; LCM, p =.243; PER, p =.113) or responder status (BRV, p =.118; LCM, p =.478; PER, p =.069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%). Significance: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

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

Abstract Objective The Prince of Wales Hospital (PWH) Real‐world Analysis of People with Drug‐Resistant Epilepsy (DRE) on PERampanel (WRAPPER) study assessed effectiveness and tolerability of adjunctive perampanel in people with DRE attending PWH. Methods This was a prospective single‐center real‐world observational study involving 70 people with DRE between July 2016 and June 2021. A post hoc analysis after the initial study period of 16 weeks assessed outcomes for an extended period up to 52 weeks. Results After 16 weeks, median dose of perampanel was 2 mg (IQR 24 mg). 50% responder rates were 40.0%, 41.5%, and 48.7% at 16, 26, and 52 weeks. Seizure freedom was 12.9%, 20.7%, and 25.6% at 16, 26, and 52 weeks. Monthly seizure frequency reduced from 3.0 (IQR 3.0–6.6) at baseline to 2.0 (IQR 2.0–6.0, p = 0.005) at 16 weeks; 2.0 (IQR 2.0–5.0, p = 0.01) at 26 weeks; and 2.0 (IQR 0.0–4.0, p = 0.018) at 52 weeks. Older age predicted 50% responders (OR 1.08, 95% CI 1.01–1.14, p = 0.048). At 16 weeks, 51.4% (36/70) had treatment‐emergent adverse effects (TEAEs). Most common was seizure exacerbation at 35.7% (25/70) followed by fatigue at 15.7% (11/70). NPI‐12 and ZBI scores indicated no increase in neuropsychiatric symptoms on perampanel. Significance Low‐dose 2–4 mg adjunctive perampanel for people with DRE conferred appreciable improvements in seizure reduction without significant neuropsychiatric adverse effects in the real‐world setting at a tertiary center in Hong Kong and had better antiseizure effect with advancing age. Plain Language Summary This real‐world study from Hong Kong found low‐dose perampanel was effective and tolerable for people with drug‐resistant epilepsy. Furthermore, perampanel was also potentially more effective with advancing age.

Abstract Background Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. Case presentation A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. Conclusion Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

Abstract Background Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies. The PerSurge trial was designed to test the clinical potential of perampanel to reduce tumor cell network connectivity and tumor growth with an extended window-of-opportunity concept. Methods PerSurge is a phase IIa clinical and translational treatment study around surgical resection of progressive or recurrent glioblastoma. In this multicenter, 2-arm parallel-group, double-blind superiority trial, patients are 1:1 randomized to either receive placebo or perampanel (n = 66 in total). It consists of a treatment and observation period of 60 days per patient, starting 30 days before a planned surgical resection, which itself is not part of the study interventions. Only patients with an expected safe waiting interval are included, and a safety MRI is performed. Tumor cell network connectivity from resected tumor tissue on single cell transcriptome level as well as AI-based assessment of tumor growth dynamics in T2/FLAIR MRI scans before resection will be analyzed as the co-primary endpoints. Secondary endpoints will include further imaging parameters such as pre- and postsurgical contrast enhanced MRI scans, postsurgical T2/FLAIR MRI scans, quality of life, cognitive testing, overall and progression-free survival as well as frequency of epileptic seizures. Further translational research will focus on additional biological aspects of neuron-tumor connectivity. Discussion This trial is set up to assess first indications of clinical efficacy and tolerability of perampanel in recurrent glioblastoma, a repurposed drug which inhibits neuron-glioma synapses and thereby glioblastoma growth in preclinical models. If perampanel proved to be successful in the clinical setting, it would provide the first evidence that interference with neuron-cancer interactions may indeed lead to a benefit for patients, which would lay the foundation for a larger confirmatory trial in the future. Trial registration EU-CT number: 2023-503938-52-00 30.11.2023.