Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes

Kwan, Patrick; Brodie, Martin J.; Laurenza, Antonio; FitzGibbon, Hannah; Gidal, Barry E.

doi:10.1016/j.eplepsyres.2015.09.002

Cited by 39 publications

(30 citation statements)

References 15 publications

(15 reference statements)

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“…Following the assessment of the European Medication Agency and some studies (European Medicines Agency, 2015;Gidal et al, 2015), carbamazepine (CBZ), phenytoin (PHT) and oxcarbazepine (OXC) were considered as EIAEDs, and eslicarbazepine acetate (ESL), phenobarbital (PB) and topiramate (TPM) as non-EIAEDs. However, as recent studies (Kwan et al, 2015) suggest that these latter drugs may affect PER efficacy, an analysis to address whether they should be considered as EIAEDs was also performed. The baseline was the three-month period prior to the initiation of PER treatment.…”

Section: Methodsmentioning

confidence: 99%

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

Garamendi-Ruíz¹,

García-García²,

Bertol-Alegre³

et al. 2016

Epileptic Disorders

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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.

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Section: Methodsmentioning

confidence: 99%

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

Garamendi-Ruíz¹,

García-García²,

Bertol-Alegre³

et al. 2016

Epileptic Disorders

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“…Briefly, PER was recently licensed for the treatment of focal and generalized epilepsies . It is a noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole proprionic acid (AMPA) receptor antagonist demonstrated efficacious in focal and generalized seizures in randomized controlled trials and clinical real‐life studies . LEV is a widely used AED, featured by a high therapeutic index and wide margin of safety compared to other AEDs .…”

Section: Introductionmentioning

confidence: 99%

“…8,9 It is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor antagonist demonstrated efficacious in focal and generalized seizures in randomized controlled trials and clinical real-life studies. [10][11][12] LEV is a widely used AED, featured by a high therapeutic index and wide margin of safety compared to other AEDs. 13 VPA is one of the oldest AED, characterized by a significant efficacy in treating epileptic seizures, but associated with several side effects.…”

Section: Introductionmentioning

confidence: 99%

Preliminary evidence about irritability in patients with epilepsy treated by perampanel as first add‐on therapy compared to levetiracetam and valproic acid

et al. 2019

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Summary Aims Irritability has been described as a frequent adverse event in patients affected by epilepsy and treated with perampanel (PER), levetiracetam (LEV), and less frequently with valproic acid (VPA). Since the questionnaire for irritability (I‐EPI) is a validated instrument to measure this psychiatric manifestation in patients affected by epilepsy, in this study we aimed at investigating the effect of PER as first add‐on therapy on I‐EPI. Moreover, we compared the effectiveness and I‐EPI scores obtained at 12‐month follow‐up visits in patients treated by PER, LEV, or VPA in order to measure irritability as a consequence of these treatments. Methods We collected data from 17 patients treated by PER, 16 patients treated by LEV, and 16 patients under VPA treatment followed for 12 months. Results We did not document significant changes of I‐EPI questionnaire between baseline and follow‐up in the PER group. As concerning the comparison of I‐EPI among PER, LEV, and VPA groups, we documented lower global scores in PER than both LEV ( P < 0.05) and VPA ( P < 0.05) groups. Moreover, patients under PER treatment showed lower scores than LEV and VPA ( P < 0.05) in I‐EPI items measuring the gentle personality, anxiety of having epileptic seizures in front of others, and irritability in thinking that they can have an epileptic seizure. Conclusions This retrospective study described a stable and possibly lower degree of irritability in patients starting PER than LEV and VPA treatments, although we documented the comparable effectiveness of PER, LEV, and VPA as first add‐on treatments in patients affected by uncontrolled epileptic seizures. However, the small sample of patients included in this study and the absence of I‐EPI scores obtained at baseline visits in LEV and VPA groups require further investigations to confirm this preliminary evidence.

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“…11 Data from a phase 3 trial show that perampanel efficacy was maintained when co-administered with carbamazepine, valproic acid, lamotrigine, and levetiracetam. Despite the known interaction between perampanel and EIAEDs (reduction in perampanel plasma concentration), addition of perampanel improved efficacy outcomes regardless of the type of concomitant AEDs.…”

mentioning

confidence: 99%

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

Tsai¹,

Leung

et al. 2017

Acta Neurol Scand

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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.

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Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes

Cited by 39 publications

References 15 publications

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

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

Preliminary evidence about irritability in patients with epilepsy treated by perampanel as first add‐on therapy compared to levetiracetam and valproic acid

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

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