Dataset Information

Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures.

ABSTRACT:

Introduction

Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A).

Methods

The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged ≥4 to <16 years as adjunctive treatment for focal (partial onset) seizures. The existing model described daily seizure counts using a negative binomial distribution, taking previous-day seizure frequencies into account, and using a mixture model to separate 'placebo-like' and 'responder' subpopulations. The model was adapted to describe aggregated monthly seizure counts for adult patients in the levetiracetam studies: daily seizure counts were only available for children in the levetiracetam studies.

Results

The levetiracetam PK/PD model successfully described both the adult and pediatric data using the same drug effect parameters, and using a model structure similar to the existing adult brivaracetam PK/PD model.

Conclusion

Simulation with the adult brivaracetam PK/PD model in combination with an existing pediatric brivaracetam population PK model allowed characterization of the dose-response curve, suggesting maximum response at brivaracetam 4 mg/kg/day dosing (capped at 200 mg/day, the maximum adult dose) in children aged ≥4 years.

SUBMITTER: Schoemaker R

PROVIDER: S-EPMC5999174 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures.

Schoemaker Rik R Wade Janet R JR Stockis Armel A

Clinical pharmacokinetics 20180701 7

<h4>Introduction</h4>Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A).<h4>Methods</h4> ...[more]

PMID: 28884437

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Project description:INTRODUCTION:There is an unmet need for well-tolerated antiepileptic drugs (AEDs) that effectively control focal onset seizures. This study aimed to evaluate the economic value of new AEDs in the treatment of focal onset seizure, with or without secondary generalization, in Finnish adults and adolescents with epilepsy, comparing brivaracetam with perampanel as adjunctive AEDs. METHODS:Economic value was assessed using cost-utility analysis. Periods of AED initiation, titration, response assessment (seizure freedom, ≥ 50% reduction, no response), switching in no response or treatment-emergent adverse events (TEAEs), and death were simulated using a discrete-event simulation model. Responses and switching were simulated based on a comprehensive Bayesian network meta-analysis. The primary modeled outcome was the 3%/year discounted incremental cost-effectiveness ratio (ICER). Discounted quality-adjusted life-years (QALYs), payer costs (year 2017 Euro) per patient, and net monetary benefit (NMB) were secondary outcomes. Probabilistic and comprehensive deterministic sensitivity analyses were conducted. RESULTS:Brivaracetam was more efficacious and had fewer TEAEs than perampanel and other AEDs. Modeled average 5-year QALYs and costs were 3.671 and €28,297 for brivaracetam and 3.611 and €27,979 for perampanel, respectively. The resulting ICER for brivaracetam versus perampanel was only €5345/QALY gained in a deterministic base case scenario. Brivaracetam had a positive NMB and high probability of cost-effectiveness of €1190 and 71% or €1944 and 80% with the assumed willingness to pay of €25,358 or €38,036/QALY gained, respectively. The primary result was robust, with a positive NMB persistent in all sensitivity analysis scenarios. When switching from brivaracetam to perampanel was excluded from the modeling or switching from perampanel to brivaracetam was included, brivaracetam was cost-saving and more effective than perampanel (dominant). CONCLUSION:These simulated comparisons demonstrated that brivaracetam was more effective and potentially also more affordable than perampanel. Thus, brivaracetam is likely a cost-effective and net beneficial alternative to perampanel for treatment of focal onset seizures. Plain language summary available for this article.

Project description:ObjectiveThis study was undertaken to evaluate safety/tolerability and efficacy of adjunctive brivaracetam (BRV) in patients on one or two concomitant antiseizure medications (ASMs) and in patients on one specific concomitant ASM.MethodsPost hoc analysis was made of double-blind trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in adults with focal seizures randomized to BRV (50-200 mg/day; approved therapeutic dose range for adults) or placebo with concomitant ASM regimen unchanged throughout a 12-week evaluation period. Outcomes were analyzed in patients on one or two concomitant ASMs, and those on concomitant carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), or valproate (VPA) only.ResultsPatients randomized to BRV with one or two concomitant ASMs, respectively (n = 181/557), reported similar incidences of treatment-emergent adverse events (TEAEs; 68.0%/66.4%), drug-related TEAEs (41.4%/41.5%), and TEAEs leading to discontinuation (6.6%/5.4%). Respective values for patients randomized to placebo with one or two concomitant ASMs (n = 95/331) were 60.0%/60.7% (TEAEs), 32.6%/30.2% (drug-related TEAEs), and 2.1%/4.5% (TEAEs leading to discontinuation). The incidences of TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation by specific concomitant ASM (CBZ, LTG, OXC, VPA) were similar to the overall incidences in patients taking one concomitant ASM. In patients on one or two concomitant ASMs, respectively, 50% responder rates were numerically higher on BRV (42.3%/36.8% [n = 175/511]) versus placebo (18.3%/19.5% [n = 93/298]). Patients with one or two ASMs on BRV (n = 175/509) versus placebo (n = 92/298) also had numerically higher 100% responder rates (BRV, 9.1%/4.5%; placebo, 1.1%/.3%) and seizure freedom (6.9%/3.7%; 1.1%/0). For patients taking concomitant CBZ, LTG, OXC, or VPA, efficacy was numerically higher with BRV (n = 54/30/27/27) versus placebo (n = 34/13/10/14-15; 50% responder rates: BRV, 31.5%/30.0%/40.7%/70.4%; placebo, 17.6%/7.7%/20.0%/33.3%; 100% responder rates: BRV, 5.6%/10.0%/11.1%/11.1%; placebo, 0 for all; seizure freedom: BRV, 3.7%/6.7%/7.4%/11.1%; placebo, 0 for all).SignificanceTherapeutic doses of BRV were efficacious and well tolerated regardless of the number of concomitant ASMs (one or two) or specific concomitant ASM (CBZ, LTG, OXC, VPA).

Project description:IntroductionEfficacy/tolerability of adjunctive brivaracetam (BRV) for focal-onset seizures (FOS) in patients aged ≥ 16 years was established in randomized controlled trials. This study aimed to evaluate the effectiveness of adjunctive BRV in patients (≥ 16 years) with FOS with/without focal to bilateral tonic-clonic seizures in daily clinical practice.MethodsA 12-month, prospective, real-world, noninterventional study in nine European countries (EP0077/NCT02687711). BRV was prescribed per clinical practice and European Summary of Product Characteristics. Eligible patients had never received BRV before inclusion. Treating physicians made the decision to prescribe BRV, independently of study participation. Primary effectiveness outcome: BRV retention rate at 12 months; secondary effectiveness outcomes: 50% responder rate, seizure freedom.ResultsA total of 544 patients received ≥ 1 BRV dose (mean age: 43.6 years; 52.8% female; mean time since diagnosis: 22.7 years). Patients had a mean of 7.3 lifetime antiseizure medications (ASMs) and median of 3.7 FOS/28 days during 3-month retrospective baseline. Median total ASM drug load (including BRV) was 3.0 at BRV initiation (n = 539) and 3.3 at study end (n = 314). At 12 months, 57.7% of 541 patients remained on BRV, 60.4% of 230 were responders (≥ 50% seizure reduction since baseline), and 13.8% of 269 were seizure-free since BRV initiation. Historical levetiracetam use appeared not to impact retention rate (56.6% of 320 and 59.3% of 221 patients with and without historical levetiracetam use, respectively). 36.0% of 544 patients had drug-related treatment-emergent adverse events (TEAEs), mostly (≥ 5% of patients) drug ineffective (11.4%) and seizure (6.3%). The three most common drug-related TEAEs leading to permanent BRV discontinuation (of 544 patients) were drug ineffective (10.1%), seizure (5.1%), and behavior disorder (3.3%).ConclusionsAdjunctive BRV was effective in clinical practice in patients with predominantly difficult-to-treat FOS, as shown by BRV retention rate of 57.7% at 12 months, which is in line with real-world retention rates for other new-generation ASMs.

Project description:ObjectiveLow-frequency fiber-tract stimulation has been shown to be effective in treating mesial temporal lobe epilepsies through activation of the hippocampal commissure in rodents and human patients. The corpus callosum is a major pathway connecting the two hemispheres of the brain; however, few experiments have documented corpus callosum stimulation. The objective is to determine the efficacy of corpus callosum stimulation at low frequencies to suppress cortical seizures.Methods4-Aminopyridine was injected in the primary motor cortex of 24 rats under anesthesia. Recording electrodes were placed in the contralateral motor cortex and hippocampus. Three pairs of stimulating electrodes were inserted into the corpus callosum along its longitudinal axis. Local field potentials were recorded 1 hour before, during, and after stimulation to determine the effect of stimulation on seizure duration. Stimulation was delivered from each pair of electrodes independently in separate experiments. Furthermore, electrical stimulation was applied to the region of the corpus callosum with the highest degree of innervation of the seizure focus to compare the efficacy of different stimulation frequencies (1-30 Hz) on seizure suppression.ResultsCorpus callosum stimulation was effective at suppressing seizures at 10 Hz by 76% (P < 0.05, n = 5) and at 20 Hz by 95% (P < 0.0001, n = 14). Stimulation at frequencies of 1 and 30 Hz did not have a significant effect on reducing the total time spent seizing (P > 0.9999, n = 5). Furthermore, stimulation was only effective at suppressing seizures when the pair of electrodes was placed within the section of corpus callosum containing fibers innervating the seizure focus. Secondarily generalized seizures in the hippocampus were eliminated when seizures in the cortical focus were suppressed.SignificanceLow-frequency fiber-tract stimulation of the corpus callosum suppresses both cortical and cortically induced hippocampal seizures in an acute model of focal cortical seizures. The stimulation paradigm is selective, as it is only effective when targeted to specific regions of the corpus callosum that project maximally to cortical regions generating the seizure activity. Selective placement of stimulation electrodes along the corpus callosum could be used as a patient-specific treatment for cortical epilepsies.

Project description:IntroductionThis article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen.MethodsThis was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation.ResultsNine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups.ConclusionBRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.

Dataset Information

Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures.

Introduction

Methods

Results

Conclusion

Publications

Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures.

Similar Datasets

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