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

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

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures

The antiepileptic drug (AED) perampanel is approved in ≥40 countries as adjunctive therapy for drug‐resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double‐blind, randomized studies of perampanel examines between‐gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme‐inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between‐gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored.     

The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist

The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5–2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co‐ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2–12 mg); perampanel is 95% protein‐bound to albumin and α1‐acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half‐life is ~105 h, whereas the calculated effective half‐life is 48 h. These half‐life values allow for once‐daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half‐life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4‐inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.     

The practical impact of altered dosing on perampanel plasma concentrations: Pharmacokinetic modeling from clinical studies

RationalePerampanel is a selective AMPA receptor antagonist approved for adjunctive therapy in patients with refractory partial-onset seizures. Perampanel is metabolized primarily via CYP3A4, yet it has a relatively long half-life of 105 h; it is, therefore, recommended that perampanel be given once daily (preferably at bedtime). Many patients occasionally have less-than-perfect adherence to their drug regimen, and given the known pharmacokinetic interactions of perampanel with commonly used enzyme-inducing antiepileptic drugs (EIAEDs), we explored the effects of a missed dose on steady-state perampanel plasma concentrations and the ramifications of “make up” doses in these patients. Although perampanel is approved for once-daily dosing, some clinicians may elect to give perampanel as a divided dose (i.e., twice daily), so we also sought to examine the pharmacokinetic impact of twice- versus once-daily dosing.MethodsPharmacokinetic simulations were performed using validated perampanel pharmacokinetic parameters, derived from 19 phase I studies in 606 subjects, to investigate the effect on perampanel plasma concentration of (1) missing a dose of perampanel followed by delayed replacement of the missed dose, (2) missing a dose followed by resumption of scheduled therapy, and (3) missing a dose in the presence/absence of carbamazepine. Simulations were done for a typical patient receiving an 8-mg once-daily or a 4-mg twice-daily dose using the nonlinear mixed effects program, NONMEM v7.2, in conjunction with PDx-pop v5.ResultsOur results corroborate that given the pharmacokinetic characteristics of perampanel, a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6–12 h later, followed by continuation of the regular schedule, may not result in any significant “spikes” in perampanel plasma concentrations. Simulations demonstrated that twice-daily dosing offered little advantage in further flattening the concentration–time profile of perampanel in the adherent patient. However, fluctuations in plasma concentrations are minimized by twice-daily dosing in patients receiving concomitant EIAEDs.ConclusionsThese pharmacokinetic simulations suggest that the long half-life of perampanel may be advantageous in conferring a relatively smooth concentration–time profile with a once-daily or twice-daily dosing, even in the presence of concomitant EIAEDs. However, the results of the present study suggest that perampanel replacement is recommended for patients taking an EIAED to mitigate the potential risks associated with reduced exposure. Confirmation of the ultimate clinical impact of these findings will require further study.     

One‐year clinical experience of perampanel in Spain: a multicentre study of efficacy and tolerability

Perampanel, a non‐competitive antagonist of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptors, is the most recent antiepileptic drug available in Spain, marketed in January 2014. It was initially approved by the European Medicines Agency as adjunctive treatment for partial‐onset seizures in patients 12 years and older, but recently also for primary generalized tonic‐clonic seizures. Although clinical trials provide essential information about the drug, they do not reflect daily clinical practice. This retrospective study shows the initial experience with perampanel in 11 Spanish hospitals during its first year post‐commercialisation. All patients who started perampanel treatment were included, but efficacy and tolerability were only assessed in those patients with a minimum follow‐up period of six months. In total, 256 patients were treated with perampanel before September 2014, and 253 had an observational period of one year. After six months, 216/256 patients (84%) continued on perampanel and 180/253 (71.1%) completed one year of treatment. The mean number of previous antiepileptic drugs used was 6.83 and the median number of concomitant antiepileptic drugs was 2. The mean perampanel dose was 7.06 mg and 8.26 mg at six and 12 months, respectively. The responder rate was 39.5% and 35.9% at both follow‐up points, respectively. Adverse events were experienced by 91/253 (35.5%) and resulted in withdrawal in 37 (14.6%). The most common adverse events were somnolence, dizziness, and irritability. We found no significant differences between concomitant use of enzyme‐inducing and non‐inducing antiepileptic drugs, regarding efficacy, adverse effects, or withdrawals. Irritability was not influenced by concomitant use of levetiracetam, relative to other drugs, but was more frequently observed in patients with a history of psychiatric problems or learning disabilities.     

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

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

Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: Results of randomized global phase III study 305

Purpose: To assess the efficacy and safety of once‐daily doses of perampanel 8 and 12 mg when added to 1–3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial‐onset seizures. Methods: Study 305 was a multicenter, double‐blind, placebo‐controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1–3 AEDs. Equal randomization to once‐daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19‐week double‐blind treatment phase comprising a 6‐week titration period, with weekly 2‐mg dose increments, followed by a 13‐week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre‐perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty‐six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent‐to‐treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent‐to‐treat analysis) was ?9.7%, ?30.5%, and ?17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was ?32.7% (8 mg), ?21.9 (12 mg), and ?8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment‐emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once‐daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial‐onset seizures. These study results also demonstrated that once‐daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.     

Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: A single-center postmarketing study

IntroductionPerampanel is an AMPA receptor antagonist recently approved for the treatment of partial and generalized epilepsies with tonic–clonic seizures as an add-on therapy.MethodsThis single-center postmarketing study retrospectively evaluated the efficacy of perampanel in patients with partial onset and other seizure types, with a special emphasis on its efficacy, safety, and tolerability.ResultsReview of medical records revealed that adequate data were available on 101 patients taking perampanel. Fifty-seven patients were female. Sixteen patients were of pediatric age range. The average dose of perampanel was 6.5 mg, and average treatment duration was 8.2 months. After treatment, median seizure frequency reduction was 50% overall, 50% in children, and 33% in adults; 44% in primary generalized, 38% in secondarily generalized, and 33% in partial seizures. Responder rate (50% seizure frequency reduction) was 51% overall, 63% in children, and 49% in adults; 60% in partial seizures, 43% in secondarily generalized tonic–clonic seizures, 53% in primary generalized tonic–clonic seizures, and 56% in other seizure types. Seizure freedom was attained in 6% of cases. Most common adverse events were sleepiness/fatigue (35%), behavioral problems (30%), and dizziness (22%). Adverse events were correlated with dosage. Average dose was 7.3 mg in patients with adverse events vs. 5.5 mg in those without adverse events. Patients who developed fatigue, cognitive decline, headaches, and weight gain were more likely to discontinue perampanel than those patients who experienced coordination issues and behavioral problems.ConclusionsThese findings suggest that perampanel is safe, well-tolerated, and effective in treatment of various types of adult and pediatric epilepsy syndromes. Fatigue, cognitive decline, headache and weight gain were the main causes of perampanel discontinuation.     

Efficacy and safety of perampanel in generalized and focal to bilateral tonic‐clonic seizures: A comparative study of Asian and non‐Asian populations

Perampanel is an approved adjunctive treatment for focal seizures with or without focal to bilateral tonic‐clonic (FBTC) seizures and generalized tonic‐clonic (GTC) seizures. We compared efficacy and safety of perampanel vs placebo in Asian and non‐Asian populations in a post hoc analysis of pooled data from 5 randomized phase 3 studies. Patients (≥12 years old) with focal + FBTC seizures received perampanel 2, 4, 8, or 12 mg or placebo; patients with GTC seizures received perampanel 8 mg or placebo (titration: 4‐6 weeks; maintenance: 13 weeks). Efficacy endpoints included median percentage change in FBTC or GTC seizure frequency per 28 days and 50% responder rate relative to baseline. Median percentage change in FBTC seizure frequency was significantly greater for perampanel 8 and 12 mg than placebo in the Asian population (median difference from placebo: ?30.32%, P = 0.0017; ?30.06%, P = 0.0008, respectively) and perampanel 4, 8, and 12 mg in the non‐Asian population (?35.07%, P = 0.0001; ?37.78%, P < 0.0001; ?34.53%, P < 0.0001, respectively). In both populations, median percentage change in GTC seizure frequency was significantly greater for perampanel 8 mg than placebo (median difference from placebo: Asian, ?37.37%, P = 0.0139; non‐Asian, ?27.04%, P = 0.0006). The 50% responder rates were significantly greater than placebo for perampanel 8 and 12 mg for FBTC seizures (Asian: 58.0%, P = 0.0017 and 58.6%, P = 0.0013, respectively; non‐Asian: 59.3%, P < 0.0001 and 54.3%, P = 0.0050, respectively) and perampanel 8 mg for GTC seizures (Asian: 57.6%, P = 0.0209; non‐Asian: 68.8%, P = 0.0329). Pooled FBTC/GTC seizure data showed generally similar patterns of response to perampanel in both populations. The most frequent treatment‐related adverse events were fatigue, irritability, dizziness, somnolence, and headache. Perampanel was effective, well tolerated, and can be considered a therapeutic option for FBTC/GTC seizures in Asian populations.     

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

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

Changes in serum perampanel concentration profile after discontinuation of carbamazepine

Aim. To evaluate changes in the pharmacokinetics of perampanel after discontinuation of carbamazepine. Methods. We enrolled 13 patients receiving perampanel who discontinued carbamazepine therapy between June 2016 and December 2018. Data on serum concentrations were obtained from the therapeutic drug monitoring database of the National Epilepsy Center (Shizuoka, Japan). To compare the pharmacokinetics of perampanel before and after discontinuation of carbamazepine, we determined the concentration/dose (CD) ratio of perampanel (serum level [ng/mL] divided by the dose [mg/kg]). The follow‐up period was set to eight weeks following the discontinuation of carbamazepine therapy. Results. The mean baseline CD ratio of perampanel was 1,247 ng/mL/mg/kg which increased markedly over time after discontinuation of carbamazepine, with a mean CD ratio at Weeks 1‐2, Weeks 3‐4, and Weeks 5‐8 of 2,683, 3,914, and 4,220, respectively. At eight weeks, the mean CD ratio of perampanel had increased by 276%. Eleven patients developed adverse events, including dizziness, somnolence, irritability, and ataxia. Five of these 11 patients required perampanel dose reduction within eight weeks after discontinuation of carbamazepine. Two patients achieved seizure‐free status at Weeks 5‐8. Conclusion. The serum perampanel concentration began to increase from one week after discontinuation of carbamazepine, and continued to rise for eight weeks. Based on these findings, we recommend frequent monitoring of serum perampanel concentration for at least eight weeks after stopping carbamazepine therapy. Monitoring is required as a guide for dose adjustment in order to achieve a safe and effective therapeutic dose of perampanel.     

Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy

Purpose: To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2‐(2‐oxo‐1‐phenyl‐5‐pyridin‐2‐yl‐1,2‐dihydropyridin‐3‐yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial‐onset seizures. Methods: Perampanel pharmacology was assessed by examining changes in intracellular free Ca²⁺ ion concentration ([Ca²⁺]_i) in primary rat cortical neurones, and [³H]perampanel binding to rat forebrain membranes. Antiseizure activity of orally administered perampanel was examined in amygdala‐kindled rats and in mice exhibiting audiogenic, maximal electroshock (MES)–induced, pentylenetetrazole (PTZ) –induced, or 6 Hz‐induced seizures. Key Findings: In cultured rat cortical neurones, perampanel inhibited α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)–induced increases in [Ca²⁺]_i (IC₅₀ 93 nm vs. 2 μm AMPA). Perampanel had a minimal effect on N‐methyl‐d ‐aspartate (NMDA)–induced increases in [Ca²⁺]_i, and only at a high concentration (30 μm ). [³H]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K_i 11.2 ± 0.8 nm ) and GYKI52466 (K_i 12.4 ± 1 μm ). In mice, perampanel showed protective effects against audiogenic, MES‐induced, and PTZ‐induced seizures (ED₅₀s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock‐induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala‐kindled rats, perampanel significantly increased afterdischarge threshold (p < 0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p < 0.05 for all measures vs. vehicle). Perampanel caused dose‐dependent motor impairment in both mice (TD₅₀ 1.8 mg/kg) and rats (TD₅₀ 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD₅₀ in rotarod test/ED₅₀ in seizure test) was 1.1, 3.8, and 1.9 for MES‐induced, audiogenic, and PTZ‐induced seizures, respectively. In rat, dog, and monkey, perampanel had a half‐life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively. Significance: These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.     

Use of perampanel in children and adolescents with Lennox–Gastaut Syndrome

AimReport the use of perampanel treatment in children with Lennox–Gastaut syndrome (LGS).MethodWe conducted a prospective study of 13 LGS patients (seven male; mean age, 12.8 years) treated with adjunctive perampanel therapy. Perampanel was initiated at 2 mg/day and titrated to a median maximum dose of 6 mg/day.ResultsAfter a mean follow-up duration of 10.8 months (range, 1–24 months), nine patients (69.2%) were responders (≥ 50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as “much improved” or “very much improved”. Four patients (30.8%) discontinued perampanel due to the lack of efficacy (n = 2) and seizure aggravation (n = 2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n = 3), behavior disturbance with agitation (n = 2), and/or fatigue (n = 2). All AEs became manageable after perampanel dosing was decreased. Improvements in cognitive function and/or behavior were reported for seven patients (53.8%). Introduction of perampanel allowed the dose reduction and/or discontinuation of other treatments in seven patients (53.8%).InterpretationPerampanel was efficacious and generally well tolerated as an adjunctive treatment for seizures associated with LGS, supporting further research in this area.     

A post hoc analysis of the long‐term safety and efficacy of perampanel in Asian patients with epilepsy

This post hoc analysis assessed the long‐term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic‐clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long‐term extension phase of 3 phase‐3 perampanel trials (study 307) or the 10‐week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double‐blind phase‐3 trials and 669 had previously received perampanel 2‐12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment‐emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre‐perampanel baseline for all focal seizures was ?28.1%, and ?51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre‐perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long‐term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase‐3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.     

Perampanel,a selective,noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor antagonist,as adjunctive therapy for refractory partial‐onset seizures: Interim results from phase III,extension study 307

Purpose: To evaluate safety, tolerability, and seizure outcome data during long‐term treatment with once‐daily adjunctive perampanel (up to 12 mg/day) in patients with refractory partial‐onset seizures. Methods: Study 307 was an extension study for patients completing the double‐blind phase of three pivotal phase III trials (studies 304, 305, and 306). The study consisted of two phases: an open‐label treatment phase (including a 16‐week blinded conversion period and a planned 256‐week maintenance period) and a 4‐week follow‐up phase. Patients were blindly titrated during the conversion period to their individual maximum tolerated dose (maximum 12 mg/day). Adverse events (AEs) were monitored throughout the study and seizure frequency recorded. The interim data cutoff date for analyses was December 1, 2010. Key Findings: In total, 1,218 patients were enrolled in the study. At the interim cutoff date, 1,186 patients were in the safety analysis set; 1,089 (91.8%) patients had >16 weeks of exposure to perampanel, 580 (48.9%) patients had >1 year of exposure, and 19 (1.6%) patients had >2 years of exposure. At the interim analysis, 840 (70.8%) patients remained on perampanel treatment. The large majority of patients (n = 1,084 [91%]) were titrated to 10 mg or 12 mg/day. Median (range) duration of exposure was 51.4 (1.1–128.1) weeks. Treatment‐emergent AEs were reported in 87.4% of patients. The most frequent were dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%). Serious AEs were reported in 13.2% of patients. In the intent‐to‐treat analysis set (n = 1,207), the frequency of all seizures decreased over the first 26 weeks of perampanel treatment in patients with at least 26 weeks of exposure to perampanel (n = 1,006 [83.3%]); this reduction was maintained in patients with at least 1 year of exposure (n = 588 [48.7%]). The overall median percent changes in seizure frequency in patients included in each 13‐week interval of perampanel treatment were ?39.2% for weeks 14–26 (n = 1,114), ?46.5% for weeks 40–52 (n = 731), and ?58.1% for weeks 92–104 (n = 59). Overall responder rates in patients included in each 13‐week interval of perampanel treatment were 41.4% for weeks 14–26 (n = 1,114), 46.9% for weeks 40–52 (n = 731), and 62.7% for weeks 92–104 (n = 59). During the blinded conversion period, the reduction in seizure frequency in patients previously randomized to placebo (?42.4%, n = 369) was similar to that in patients previously randomized to perampanel (?41.5%, n = 817). Significance: Consistent with pivotal phase III trials, these interim results demonstrated that perampanel had a favorable tolerability profile in patients with refractory partial‐onset seizures over the longer term. The decrease in seizure frequency was consistent and maintained in those patients over at least 1 year of perampanel exposure.     

Adjunctive lacosamide for focal epilepsy: an open‐label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes

Aims. To evaluate the safety and effectiveness of lacosamide in a real‐life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Methods. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open‐label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12‐week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12‐week maintenance period. Primary outcomes were incidence of treatment‐emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. Results. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure‐free. Conclusion. Flexible lacosamide dosing in this open‐label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.     

Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized,placebo‐controlled study

Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society     

Schwere Nebenwirkungen und Sturzanfälle unter Perampanel

Perampanel was recently introduced as a promising drug for the therapy of refractory epilepsy and possibly other diseases of the central nervous system, such as Parkinson’s disease. This non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist shows a new mode of action. This article reports on two children with therapy-refractory epilepsy treated with perampanel as an add-on therapy in whom a deterioration of seizure control and bioelectrical status in the EEG occurred with a several-fold increase of collapse attacks. After withdrawal of perampanel these side effects were reversible. Perampanel is a highly potent drug but can cause seizure aggravation in rare cases.