Refractory Partial-onset Seizures Research Articles

Development and Validation of HPLC-FLD Analysis of Perampanel in MEPS-Processed Rat Plasma Sample

Perampanel, a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is registered for the adjunctive treatment of patients (aged ≥ 12 years) with refractory partial-onset seizures. A simple high-performance liquid chromatographic method fluorescence detection (HPLC-FLD) was developed to analyze perampanel in rats’ plasma and validated for bioanalytical purposes. Rats’ plasma (50 µL) was processed by microextraction packed sorbent (MEPS). The analytes were separated using a Hypersil Gold octadecyl silane column (250 × 4.6 mm internal diameter, 5 μm particle size) with isocratic elution. A mobile phase consisting of acetonitrile–methanol–water (275:275:450, v/v/v; containing 50 µL triethylamine and pH adjusted to 3.25 with orthophosphoric acid) was used in this analysis. The flow rate was 1.25 mL/min. Analytes were monitored at an excitation wavelength of 285 nm and an emission wavelength of 430 nm. The linearity range for this validated method was from 3.75 to 300 ng/mL. No endogenous peaks were found in the elution of analytes in drug-free rats’ plasma. Intra- and inter-batch reproducibility studies demonstrated accuracy and precision within the acceptance criteria. The results indicate that the present method is simple, selective, reproducible, and suitable for the analysis of perampanel in small volume samples. The robustness of the method was accessed using MODDE® design of experiments software version 12.5.

ID: 208947 Ultrashort Microscopic Magnetic Vagal Stimulation

Electrical stimulation of the cervical vagus nerve is an emerging treatment field for various central nervous system disorders. Invasive electrical Vagus nerve stimulation (VNS) is an FDA-approved add-on treatment to medication for refractory partial-onset seizures in patients 12 years of age and older. However, only approximately 40-50% of patients experience a marked seizure reduction of 50% or more than seizures before treatment [1]. The effects of VNS on neurotransmitter systems, including the noradrenergic system originating from the locus coeruleus and the serotonergic system from the dorsal raphe nucleus, have been reported in experimental settings. The therapeutic effect of VNS in the brain is linked to the stimulation of large diameter afferent fibers. These large myelinated afferent fibers, terminating in the nucleus tractus solitarius in the brainstem, are assumed to deliver the therapeutic effect through further projections into the other brain areas. Non-selective stimulation results in inadvertent activation of efferent fibers that innervate a wide range of peripheral organs resulting in adverse effects [2] with a rare but severe risk of bradyarrhythmia and asystole.

PND43 THE BURDEN OF PEDIATRIC PARTIAL ONSET SEIZURES: A REVIEW OF THE LITERATURE

To better understand the burden of epilepsy among 2- to 12-year-olds, we conducted a targeted literature review summarizing incidence, prevalence, healthcare costs, utilization, and quality of life (QOL). We searched PubMed for English-language publications reporting on children 2-12 years with either partial onset seizures (POS) or primary generalized tonic-clonic seizures, published in the United States since 2008. Data on incidence, prevalence, healthcare costs, utilization, and QOL outcomes were extracted. Findings on POS are presented here. 3,020 studies were found; 48 were included in this review. Incidence of POS was 23.2-47.1 per 100,000 children per year; prevalence was 2.0 per 1,000 children, and ranged from 1.6 to 2.6 per 1,000 in patients of any age. Annual total healthcare costs among patients of any age with POS ranged from $18,369-38,549, and were approximately two times higher in refractory POS. First-year total healthcare costs for children with POS were $19,883. Patients of any age with POS had about 10 outpatient visits, 24 procedures, 2 hospitalization days (less than 1 epilepsy-related) and 30 medication dispensing events (7 epilepsy-related) per year. Eight studies reported on QOL burden; 6 on cognitive difficulties (language, visuospatial, and memory development delays) and 4 on behavioral disorders (anxiety, depression, and attention-deficit disorder). Children with POS scored below average on cognitive assessments, and up to 42%, 16%, and 19% had depression, anxiety, and attention-deficit disorder, respectively. Incidence and prevalence of POS in children are high, similar to that of childhood type 1 diabetes; further, healthcare cost, utilization, and QOL burdens facing patients with POS are significant, especially among the group with refractory seizures. Most studies did not report outcomes aggregated by age groups or did not stratify by POS, which was true for utilization. Future studies focused exclusively on children with POS would be useful to more precisely describe the burden.

An Investigation into Retigabine (Ezogabine) Associated Dyspigmentation in Rat Eyes by MALDI Imaging Mass Spectrometry.

Retigabine (RTG) is an antiepileptic drug approved as an adjunctive treatment for refractory partial-onset seizures in adults. In April 2013, the Food and Drug Administration issued a warning that RTG could cause changes in retinal pigmentation and discoloration of skin, resulting in a blue appearance. As part of a larger preclinical effort to gain a mechanistic understanding as to the origins of retinal pigment changes associated with RTG, we conducted a long-term repeat dosing study in rats. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was used to determine the distribution of RTG and its metabolites in the rat eye following 13 and 39 weeks of dosing. IMS revealed the presence of RTG, a previously characterized N-acetyl metabolite of RTG (NAMR), and several species structurally related through the dimerization of RTG and NAMR. These species were highly localized to the melanin-containing layers of the uveal tract of the rat eye including the choroid, ciliary body, and iris, suggesting that the formation of these dimers occurs from melanin bound RTG and NAMR. Furthermore, several of the RTG-related dimers have UV absorbance which give them a purple color in solution. We propose that the melanin binding of RTG and NAMR effectively concentrates the two compounds to enable mixed condensation reactions to occur when the binding provides the proper geometry in the redox environment of the uveal tissues. High lateral resolution images illustrate that the blood-retinal barrier effectively restricts retinal access to RTG-related compounds. The spatial information provided by MALDI IMS was critical in contextualizing the homogenate concentrations of key RTG-related compounds and helped provide a basis for the mechanism of dimer formation.

Long-term tolerability, safety and efficacy of adjunctive perampanel in the open-label, dose-ascending Study 231 and extension Study 233 in Japanese patients with epilepsy

PurposeTo evaluate long-term tolerability, safety and efficacy of adjunctive perampanel in a Phase II, multicentre, open-label, dose-ascending Study 231 (NCT00849212) and its extension (Study 233; NCT00903786) in Japanese patients with refractory partial-onset seizures (POS), with/without secondarily generalised seizures. MethodsIn Study 231, patients received adjunctive perampanel ≤12 mg/day during a 10-week treatment period. Patients completing Study 231 could enter Study 233 (≤316-week treatment period). Assessments included monitoring of treatment-related treatment-emergent adverse events (TEAEs), median percent change in seizure frequency per 28 days, 50% responder and seizure-freedom rates. During Study 231, a pharmacokinetic analysis assessed the effects of enzyme-inducing antiepileptic drugs. ResultsOverall, 23/30 (76.7%) patients completed Study 231; 21/30 (70.0%) received perampanel ≥8 mg/day and 10/30 (33.3%) achieved a maximum tolerated dose of 12 mg/day. Median percent change in seizure frequency per 28 days was –35.0%. 50% responder rate was 37.0%; 4 (13.3%) patients achieved seizure freedom. Twenty-one patients entered Study 233. Mean duration of exposure was 195 weeks; 9 (42.9%) patients received perampanel for ≤208 weeks. Seizure control was sustained for 316 weeks in 3/21 (14.3%) patients; 2 achieved seizure freedom. Treatment-related TEAEs were tolerable; the most common was dizziness (Study 231, 53.3%; Study 233, 14.3%). Mean perampanel plasma concentrations were lower with concomitant carbamazepine vs non-inducers (152.7 ng/mL vs 389.4 ng/mL across perampanel groups); small patient numbers for non-inducers (n = 2) should be considered when interpreting these data. ConclusionAdjunctive perampanel demonstrated a favourable safety profile and long-term tolerability in Japanese patients with refractory POS for ≤316 weeks.

Measuring Health-Related Quality of Life in Tuberous Sclerosis Complex - Psychometric Evaluation of Three Instruments in Individuals With Refractory Epilepsy.

Tuberous sclerosis complex (TSC) is a rare genetic disease associated with significant disease burden and considerable impact on health-related quality of life (HRQL). Currently no disease-specific clinical outcome assessments evaluate HRQL in individuals with TSC. A multi-center phase III study EXIST-3 (NCT01713946) assessed the efficacy and safety of two trough exposure ranges (Low exposure, LE: 3–7 ng/mL and high exposure, HE: 9–15 ng/mL) of adjunctive everolimus in patients aged 2–65 years with TSC and refractory partial-onset seizures (N = 366). Three age-specific HRQL measures were included as secondary endpoints including: quality of life in childhood epilepsy (QOLCE; caregiver-report for aged 2- < 11), the Quality of Life in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48; self-report, aged ≥ 11- < 18), and the Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P; self-report, aged ≥ 18). Intellectual ability was evaluated using the Wechsler Non-Verbal (WNV) Scale of Ability. Post hoc analyses were performed on the core phase primary data from EXIST-3 to evaluate the psychometric properties of the HRQL measures and calculate meaningful change estimates. Results showed that a significant subset of the trial sample (4–21 year olds) scored in the intellectual disability range, as assessed by the WNV. Psychometric analyses of the three epilepsy measures (including reliability, validity, and ability to detect change) supported the appropriateness for use in TSC. Distribution-based meaningful change estimates were generated for each HRQL measure, with estimates for the QOLIE-31-P total score largely consistent with the published literature. To our knowledge, this is the first evaluation using clinical trial data to establish the psychometric properties of the QOLCE, QOLIE-AD-48, and QOLIE-31-P for use in individuals with TSC. These findings increase confidence in the measures as valid and reliable for use in clinical trials and future research in patients with TSC.

Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials

ObjectiveIn the absence of randomized clinical trials (RCTs) assessing the relative efficacy of antiepileptic drugs (AEDs), meta-analyses are useful resources for informing treatment choices. This meta-analysis assesses the relative efficacy and tolerability of AEDs for adjunctive treatment of refractory partial onset seizures (POS). MethodsA systematic literature review was conducted to identify pivotal AED trials serving as the basis for US Food and Drug Administration (FDA) approval. Inclusion criteria: 1) double-blind, placebo-controlled, parallel-group design, with 8- to 14-week maintenance period; 2) enrolled patients ≥16years with refractory POS, including complex partial seizures; 3) study was conducted between 1993 and 2013; and; 4) patients received FDA-approved dosage. Outcomes analyzed: 1) 50% responder rate (≥50% reduction from baseline in seizure frequency); 2) seizure freedom (proportion of seizure-free patients); and 3) discontinuation due to adverse events (AEs). DerSimonian and Laird random-effects model was used to derive odds ratios (OR) and 95% confidence intervals (CI). ResultsA total of 29 publications for 11 AEDs (eslicarbazepine, ezogabine, gabapentin, lacosamide, levetiracetam, perampanel, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide) were included in the meta-analysis. Tiagabine 56mg/day (OR 8.82, 95% CI: 2.77–28.11), pregabalin 600mg/day (OR 8.08, 95% CI: 5.45–11.98), and vigabatrin 3000mg/day (OR 6.23, 95% CI: 1.46–26.20) had the highest OR versus placebo of 50% response. The odds of seizure freedom were ≥7 times greater than placebo for levetiracetam 3000mg/day (OR 11.00, 95% CI: 2.08–58.06), vigabatrin 3000mg/day (OR 7.41, 95% CI: 1.31–41.84), and ezogabine 1200mg/day (OR 7.09, 95% CI: 0.36–58.06). Patients were more likely to discontinue any AED (except low-dose pregabalin) than placebo. ConclusionIn this meta-analysis of >9000 patients, those treated with AEDs were more likely than placebo to achieve seizure response or freedom. Patients receiving pregabalin, tiagabine, and vigabatrin had the highest odds of ≥50% reduction in seizures, and patients receiving ezogabine, levetiracetam, and vigabatrin had the highest odds of seizure freedom.

Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures

ObjectiveTo evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults. MethodsThis was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity. ResultsThe analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). However, the incidence of depression and suicidality-related TEAEs was significantly higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was significantly higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, aphasia, and bradyphrenia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively. ConclusionsIn phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. However, the incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were significantly higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.

Influence of titration schedule and maintenance dose on the tolerability of adjunctive eslicarbazepine acetate: An integrated analysis of three randomized placebo-controlled trials

ObjectiveTo examine the influence of titration schedule and maintenance dose on the incidence and type of treatment-emergent adverse events (TEAEs) associated with adjunctive eslicarbazepine acetate (ESL). MethodsData from three randomized, double-blind, placebo-controlled trials were analyzed. Patients with refractory partial-onset seizures were randomized to maintenance doses of ESL 400, 800, or 1200mg QD (dosing was initiated at 400 or 800mg QD) or placebo. The incidence of TEAEs was analyzed during the double-blind period (2‐week titration phase; 12-week maintenance phase), according to the randomized maintenance dose and the titration schedule. Results1447 patients were included in the analysis. During the first week of treatment, 62% of patients taking ESL 800mg QD had ≥1 TEAE, vs 35% of those taking 400mg QD and 32% of the placebo group; dizziness, somnolence, nausea, and headache were numerically more frequent in patients taking ESL 800mg than those taking ESL 400mg QD. During the double-blind period, the incidences of common TEAEs were lower in patients who initiated ESL at 400mg vs 800mg QD. For the 800 and 1200mg QD maintenance doses, rates of TEAEs leading to discontinuation were lower in patients who began treatment with 400mg than in those who began taking ESL 800mg QD. ConclusionsInitiation of ESL at 800mg QD is feasible. However, initiating treatment with ESL 400mg QD for 1 or 2 weeks is recommended, being associated with a lower incidence of TEAEs, and related discontinuations. For some patients, treatment may be initiated at 800mg QD, if the need for more immediate seizure reduction outweighs concerns about increased risk of adverse reactions during initiation.

A pooled post-hoc analysis of change in depressive symptoms in patients with refractory partial-onset seizures treated with eslicarbazepine acetate as adjuntive therapy

A pooled post-hoc analysis of change in depressive symptoms in patients with refractory partial-onset seizures treated with eslicarbazepine acetate as adjuntive therapy

Felbamate as an add-on therapy for refractory partial epilepsy

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials.

To assess the safety and efficacy of once-daily (QD) adjunctive eslicarbazepine acetate (ESL). This post-hoc pooled analysis of three randomized, placebo-controlled trials (2093-301, -302, -304) involved adults with refractory partial-onset seizures (POS) receiving 1-3 antiepileptic drugs (AEDs). All studies included 8-week baseline, 2-week titration, and 12-week maintenance periods. Patients were randomized equally to placebo, ESL 400mg (studies 301, 302), 800mg, or 1200mg QD. The primary endpoint was standardized seizure frequency (SSF; per 4weeks); secondary endpoints included responder rates (maintenance period), and incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths. The safety and efficacy analysis populations totaled 1447 and 1410 patients, respectively. SSF was significantly reduced versus placebo with ESL 800mg (p=0.0001) and 1200mg (p<0.0001) but not 400mg (p=0.81). There were no significant interactions between treatment effect and age, gender, race/ethnicity, geographic region, epilepsy duration, or concomitant AED use. Incidences of TEAEs and TEAEs leading to discontinuation increased with ESL dose. Incidences of the most frequent TEAEs were lower for patients who initiated dosing at 400 versus 800mg QD, regardless of titration regimen and maintenance dose. SAE incidence was <10%; there were 3 deaths (placebo, n=2; ESL 800mg, n=1). ESL (800 and 1200mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.

Psychometric evaluation of quality of life measures in a three-arm, randomized, double-blind, placebo-controlled phase III study of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures (EXIST-3) (P2.057)

Psychometric evaluation of quality of life measures in a three-arm, randomized, double-blind, placebo-controlled phase III study of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures (EXIST-3) (P2.057)

Brivaracetam: An Adjunctive Treatment for Partial-Onset Seizures.

Brivaracetam is an analogue of levetiracetam that is Food and Drug Administration-approved for adjunctive treatment of partial-onset seizures in patients 16 years and older. In placebo-controlled trials adjunct brivaracetam demonstrated efficacy in reducing the frequency of seizures. The most commonly reported adverse effects are somnolence, dizziness, and fatigue. Clinical trials have evaluated brivaracetam for safety and efficacy in adjunctive treatment of partial-onset seizures in patients 16 years and older for up to 16 weeks. Brivaracetam's mechanism is similar to that of levetiracetam but with greater receptor binding affinity on synaptic vesicle protein 2A and inhibitory effects on sodium channels. Clinically significant differences between these agents are undetermined. Brivaracetam is available as oral tablets, oral solution, and intravenous solution. The Food and Drug Administration-approved dose is 50 mg twice daily, and titration is not required. Brivaracetam does not need dose adjustment for renal impairment and has minimal drug-drug interactions. Current limitations of brivaracetam include lack of head-to-head trials, limited long-term safety and efficacy data, and cost. Overall, brivaracetam is a viable adjunct therapeutic option for refractory partial-onset seizures in those who have failed conventional therapies.

New developments in the management of partial-onset epilepsy: role of brivaracetam.

Currently, a number of novel anticonvulsant drugs, the so-called third generation, are in various stages of development. Several of them are already available or in ongoing clinical trials. These new compounds should take advantage of new insights into the basic pathophysiology of epileptogenesis, drug metabolism and drug interactions. Many of them still need to be further evaluated mainly in real-world observational trials and registries. Among newer anticonvulsant drugs for partial-onset seizures (POSs), rufinamide, lacosamide, eslicarbazepine and perampanel are those new treatment options for which more substantial clinical evidence is currently available, both in adults and, to some extent, in children. Among the newest anticonvulsant drugs, brivaracetam, a high-affinity synaptic vesicle protein 2A ligand, reported to be 10- to 30-fold more potent than levetiracetam, is highly effective in a broad range of experimental models of focal and generalized seizures. Unlike levetiracetam, brivaracetam does not inhibit high-voltage Ca2+ channels and AMPA receptors and appears to inhibit neuronal voltage-gated sodium channels playing a role as a partial antagonist. Brivaracetam has a linear pharmacokinetic profile, is extensively metabolized and is excreted by urine (only 8%–11% unchanged). It does not seem to influence the pharmacokinetics of other antiepileptic drugs. It was approved in the European Union in January 2016 and in the US in February 2016 as an adjunctive therapy for the treatment of POS in patients older than 16 years of age. To date, its clinical efficacy as adjunctive antiepileptic treatment in adults with refractory POS at doses between 50 and 200 mg daily has been extensively assessed in two Phase IIb and four Phase III randomized controlled studies. Long-term extension studies show sustained efficacy of brivaracetam. Overall, the drug is generally well tolerated with only mild-to-moderate side effects. This is true also by intravenous route. Brivaracetam has not yet been evaluated as monotherapy or in comparison with other new anticonvulsant drugs.

Topiramate Extended Release: A Review in Epilepsy

Once-daily oral topiramate extended release (USL255; hereafter referred to as topiramate XR) [QUDEXY(®) XR] is approved in the USA for use as initial monotherapy and adjunctive therapy in patients aged ≥2years with partial-onset seizures (POS) or primary generalized tonic-clonic seizures and as adjunctive therapy in patients aged ≥2years with seizures associated with Lennox-Gastaut syndrome. Compared with twice-daily topiramate immediate release at the same total daily dose, topiramate XR provided bioequivalent exposure, an extended absorption rate (permitting convenient once-daily dosing) and more constant therapeutic plasma concentrations (potentially minimizing topiramate-associated adverse events). Switching between the two formulations did not affect the maintenance of topiramate concentrations. Moreover, the contents of a topiramate XR capsule may be sprinkled on to soft food for patients who have difficulty swallowing. In a multinational phase III study in adults with refractory POS, adjunctive topiramate XR was associated with significantly greater improvements from baseline in weekly median seizure frequency and the proportion of patients achieving a ≥50% reduction in seizure frequency compared with placebo. These benefits were sustained during a 55-week open-label extension study. Adjunctive topiramate XR was generally well tolerated in these studies, with the majority of treatment-emergent adverse events being mild or moderate in intensity. In conclusion, current evidence suggests once-daily topiramate XR extends the treatment options currently available for patients aged ≥2years with epilepsy, with its dosing regimen potentially delivering tolerability and adherence advantages over AEDs that require more frequent administration.

Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial-onset seizures: pooled analysis of clinical trials.

AimsTo evaluate the impact of perampanel and demographics on clearance of concomitant antiepileptic drugs (AEDs), in patients with refractory partial‐onset seizures.MethodsPooled data from three Phase III clinical studies with adjunctive perampanel were used. Blood samples for evaluation of 11 concomitant AEDs were taken during baseline (before perampanel initiation), and at weeks 10, 14, and 19 during the maintenance phase of perampanel treatment (2–12 mg/day, once daily at bedtime). Models estimating apparent clearance of each concomitant AED were fitted to the data, and the effects of perampanel and demographic variables on clearance were determined. Final models were assessed with goodness of fit plots including population predictions and individual predictions against observations.ResultsNo significant impact of perampanel on clearance was found for clonazepam (n = 81), levetiracetam (n = 330), phenobarbital (n = 54), phenytoin (n = 90), topiramate (n = 226) or zonisamide (n = 93). Statistically significant, but small and not clinically relevant increases in model‐predicted clearance were detected for carbamazepine (+4.3% with 12 mg perampanel; n = 379), clobazam (+3.4% males, +7.7% females, 12 mg; n = 114), lamotrigine (+9.3%, 12 mg; n = 356), and valproic acid (+5.0%, 12 mg; n = 349). Oxcarbazepine clearance was reduced (26%; n = 200), but the clinical relevance is unclear as levels of the active metabolite (the monohydroxy derivative of oxcarbazepine) were not measured.ConclusionsPopulation PK data show that perampanel (2–12 mg/day, once daily at bedtime) has no relevant impact on the clearance of the most commonly used concomitant AEDs.

Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures.

The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults. Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status. Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed. The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

An Indirect Comparison of Selected Adjunctive Treatments for Refractory Partial Onset Seizures (POS): Does Evidence Matter? (P2.060)

An Indirect Comparison of Selected Adjunctive Treatments for Refractory Partial Onset Seizures (POS): Does Evidence Matter? (P2.060)

Seizure Freedom with YKP3089 as Adjunctive Therapy for Refractory Partial-Onset Seizures in Double-Blind Placebo-Controlled Trials (P2.019)

Seizure Freedom with YKP3089 as Adjunctive Therapy for Refractory Partial-Onset Seizures in Double-Blind Placebo-Controlled Trials (P2.019)