Brivaracetam Research Articles

Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials

Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area. We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130). A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400mg/d was top-ranked, followed by RTG 1200mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100mg/d leading, followed by CNB 400mg/d. Regarding tolerability, LCM 600mg/d had the lowest ranking, followed by CNB 400mg/d. For the safety outcome of AEs, ESL 1200mg/d was ranked lowest, followed by CNB 400mg/d. Regarding SAEs, LCM 400mg/d was ranked lowest, followed by RTG 1200mg/d. ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS. None.

Brivaracetam and topiramate serum levels during pregnancy and delivery: a case report and a review of literature

BackgroundAn increasing use of newer antiseizure medication (ASM) such as SV2A ligand brivaracetam is observed. However, data on newer antiseizure medication and therapeutic drug monitoring during pregnancy is scarce.MethodsTherapeutic drug monitoring of brivaracetam (BRV) and topiramate (TPM) serum levels were performed during pregnancy, delivery and in the umbilical cord blood at delivery in a 34-year-old female patient with severe drug-resistant epilepsy.ResultsDuring pregnancy, the serum levels of brivaracetam and topiramate remained stable. At 39th week of pregnancy, the patient gave birth to a healthy daughter. 1.5 h after the last ASM intake, the penetration rate measured in umbilical cord blood was 45% lower for BRV and 35% lower for TPM.ConclusionsWhile the pharmacokinetics of topiramate are well known and its use during pregnancy should only be undertaken under special circumstances, there have been few studies on newer ASM in pregnancy such as brivaracetam. Based on our results and other case reports of BRV use during pregnancy, further studies are necessary to confirm its pharmacokinetics and safety during pregnancy.

Effectiveness and tolerability of brivaracetam in patients with epilepsy stratified by comorbidities and etiology in the real world: 12-month subgroup data from the international EXPERIENCE pooled analysis.

To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies. EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12months. Analyses were performed for all adult patients (≥ 16years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE]). At 12months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively. BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE.

Brivaracetam exposure-response predictions in pediatric patients from age 1 month: Extrapolation of levetiracetam adult-pediatric scaling to brivaracetam

BackgroundAn adult population pharmacokinetic/pharmacodynamic (PK/PD) model for the antiseizure medication (ASM) brivaracetam (BRV) was previously extended to children aged 4–16 years by using a pediatric BRV population PK model. Effects were scaled using information from a combined adult-pediatric PK/PD model of a related ASM, levetiracetam (LEV). ObjectiveTo scale an existing adult population PK/PD model for BRV to children aged 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, and to predict the effective dose of BRV in children aged 1 month to < 4 years using the adult BRV PK/PD model modified for the basal seizure rate in children. Material and methodsAn existing adult population PK/PD model for BRV was scaled to children aged from 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, an ASM binding to the same target protein as BRV. An existing adult-pediatric PK/PD model for LEV was extended using data from UCB study N01009 (NCT00175890) to include children as young as 1 month of age. The BRV population PK model was updated with data up to 180 days after first administration from BRV pediatric studies N01263 (NCT00422422) and N01266 (NCT01364597). PK and PD simulations for BRV were performed for a range of mg/kg doses to predict BRV effect in pediatric participants, and to provide dosing recommendations. ResultsThe extended adult-pediatric LEV PK/PD model was able to describe the adult and pediatric data using the same PD model parameters in adults and children and supported the extension of the adult BRV PK/PD model to pediatric patients aged 1 month to < 4 years. Simulations predicted exposures similar to adults receiving BRV 100 mg twice daily (b.i.d.), when using 3 mg/kg b.i.d. for weight < 10 kg, 2.5 mg/kg b.i.d. for weight ≥ 10 kg and < 20 kg, and 2 mg/kg b.i.d. for weight ≥ 20 kg in children aged 1 month to < 4 years. PK/PD simulations show that maximum BRV response is expected to occur with 2–3 mg/kg b.i.d. dosing of BRV in children aged 1 month to < 4 years, with an effective dose of 1 mg/kg b.i.d. for some participants. ConclusionDevelopment of an adult-pediatric BRV PK/PD model allowed characterization of the exposure-response relationship of BRV in children aged 1 to < 4 years, providing a maximal dose allowance based on weight.

Conversion to Brivaracetam Monotherapy in Clinical Practice: A Retrospective Study.

The study aimed to evaluate the effectiveness and safety of brivaracetam (BRV) as conversion monotherapy in adults with focal epilepsy treated in the context of real-world clinical practice. This was a retrospective, observational, non-interventional study in adults with focal epilepsy who converted to BRV monotherapy following the withdrawal of background antiseizure medications (ASMs). Primary effectiveness outcome was the retention rate of BRV as single ASM at 6 and 12months. Secondary outcomes included the 6- and 12-month rates of seizure freedom. Safety and tolerability outcomes included the frequency and type of adverse events (AEs) and the occurrence of treatment discontinuation due to AEs. A total of 44 participants with a median age of 63.5 (interquartile range 44-73.5) years were included; 17 subjects were seizure free at baseline, and 9 of them switched from levetiracetam because of lack of tolerability. The retention rate of BRV monotherapy was 88.6% (39/44) at 6months and 83.9% (26/31) at 12months. The rates of seizure freedom were 72.7% (32/44) in subjects with 6-month follow-up and 58.1% (18/31) in subjects with 12-month follow-up. The median maintenance dosage of BRV monotherapy was 150 (100-200) mg/day at 6months and 125 (100-200) mg/day in subjects with 12-month follow-up. Adverse events were recorded in 6/44 (13.6%) participants and led to BRV discontinuation in 2/44 (4.5%) cases. The reported AEs were somnolence (n = 3), fatigue (n = 2), and irritability (n = 1); no serious AEs were experienced. In 21/44 (47.7%) participants, BRV monotherapy resulted from the direct switch from levetiracetam. The rates of treatment retention and seizure freedom at 6 and 12months were higher among people who switched from levetiracetam to BRV monotherapy. Brivaracetam may be a valuable treatment of focal seizures in people who converted to monotherapy in a real-life setting.

Value of drug level concentrations of brivaracetam, lacosamide, and perampanel in care of people with epilepsy.

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

The impact of brivaracetam on cognitive processes and anxiety in various experimental models.

Memory deficits and anxiety symptoms are undesirable effects that occur in epilepsy patients. They may be associated with the pathophysiology of the disease but also with anticonvulsant therapy. Brivaracetam (BRV) is one of the newest antiseizure drugs. It acts as a ligand for synaptic vesicle glycoprotein 2A (SV2A), which may play a significant role in cognitive processes. Although BRV has a favorable safety profile, its central side effects remain unclear. Hence, this study aimed to evaluate the effect of BRV on various types of memory and anxiety in rats. BRV was given to adult male Wistar rats (n = 80) via gastric tube as a single dose (6 mg/kg or 20 mg/kg) or chronically (6 mg/kg). The effect of the drug on spatial memory was evaluated in the Morris water maze (MWM), fear-learning by passive avoidance (PA), and recognition memory with novel object recognition (NOR). The elevated plus maze (EPM) was used to assess anxiety-like behaviors. The impact of BRV on memory is dose-dependent and mainly high doses may alter retrieval memory and fear-learning. Sub-chronic administration also impaired retrieval and spatial memory in animals. Moreover, chronic BRV may increase anxiety levels in rats but did not affect recognition memory. BRV may cause transient memory deficits as well as anxiety disturbances. However, the results are varied and depend on the type of memory, used dose, and duration of administration.

Antioxidant Effect of Levetiracetam and Brivaracetam Acting on Presynaptic SV2A Receptors: An In-vitro Study

Introduction: Epilepsy is a serious psychological condition associated with social stigma, psychiatric co-morbidity, and a high economic burden. It is pertinent to develop novel treatment methods given the ever-evolving nature of the disease. Recently, various newer Antiepileptic Drugs (AEDs) have been under study, among which a newer targeted modality consists of SV2A receptors. Aim: To compare the antioxidant properties or free radical scavenging activity of the newer heterogeneous AEDs acting on the SV2A receptors, namely Levetiracetam (LEV) and Brivaracetam (BRV). Materials and Methods: This in-vitro study was conducted at Department of Pharmacology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India from July 2021 to August 2021. The study evaluated the antioxidant properties of LEV and BRV using various assays such as the Ferric Reducing Antioxidant Power (FRAP) test, DPPH (1,1-diphenyl-2-picrylhydrazyl) assay, Nitric Oxide (NO) radical scavenging assay, Superoxide Dismutase activity (SOD), and catalase activity. The obtained results were expressed using specific formulas related to the absorbance of the respective chemicals, along with the percentage of inhibition, and have been tabulated in Microsoft excel Sheet Version 16.16.27. Halfmaximal Inhibitory Concentration (IC50) values were calculated using scatter plot graphs. Results: The FRAP values for LEV were reported to be significantly higher compared to BRV at concentrations of 20, 40, 60, 80 μg/mL, while at 100 μg/mL, BRV showed better ferric reducing activity. Although both drugs exhibited antioxidant activity, the results clearly identified LEV as a better NO radical scavenger, with a percentage of inhibition reaching up to 80.52%. During the SOD assay, the percentage inhibition of superoxide generation by LEV was found to be 99.02%, while that of BRV was 97.07% at a concentration of 100 μg/mL. LEV (0.573) also showed a higher degradation of H2O2 per minute than BRV (0.065) at a concentration of 100 μg/mL. Conclusion: The results showed that both drugs, BRV and LEV, exhibited significant antioxidant capacity. However, LEV demonstrated increased antioxidant potency and efficacy compared to BRV.

A Prospective Post-Marketing Observational Study of Brivaracetam in People With Focal Epilepsy.

We evaluated the effectiveness and tolerability of brivaracetam (BRV), an adjunctive antiseizure medication, as a treatment for focal epilepsy in adults. In this prospective study, we enrolled 51 participants from 3 sites across Canada. At 6 months, 68% (26/38) of participants were still taking BRV, among whom 35% (8/23) attained seizure freedom and 48% (11/23) saw their seizure frequency reduced by over 50%. We did not measure any significant change in irritability, quality of life, depression, and anxiety while treated with BRV. Our findings suggest BRV is effective in reducing seizure frequency among adults with focal epilepsy.

Efficacy and Safety of Brivaracetam in Persons With Epilepsy in a Real-World Setting: A Prospective, Non-Interventional Study.

Epilepsy stands out as one of the most prevalent neurological conditions. Brivaracetam (BRV) is a noteworthy antiseizure medication (ASM) distinguished by its pronounced and selective interaction with the synaptic vesicle protein 2A (SV2A) within the brain. Prior investigations, including regulatory trials, post-marketing assessments, and comparative meta-analyses, have consistently underscored BRV's equivalency in efficacy and superior tolerability when pitted against other antiseizure drugs. This study aimed to evaluate the effectiveness, safety, and acceptability of BRV in treating epileptic patients in the Pakistani population. This prospective observational study, conducted in Pakistan from February to December 2022, employed a non-probability consecutive sampling technique. This study included 368 adult patients diagnosed with epilepsy, with a focus on those aged 18 and above experiencing focal seizures. Demographic data, clinical history, seizure types, and epilepsy profiles were recorded. Patients were administered BRV (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) monotherapy therapy under physician guidance and followed up for three months. The study assessed changes in seizure frequency, side effects, and drug resistance at baseline, 14th day, and 90th day. Safety aspects were monitored, including documenting any adverse effects associated with BRV therapy. A total of 368 epileptic patients were included in this study, of which 287 (61.3%) were males and 181 (38.7%) were females. The mean age was 32.91±17.11 years. The mean number of seizures at the baseline visit was 5.74±6.21, at 14 days was 2.89±3.84 and at 90 days was 1.73±5.01 (p<0.001). Overall, a more than 50% reduction in seizure episodes was achieved in 178 (56.3%) patients at day 90, and less than 50% reduction in seizure episodes was achieved by 95 (26.8%) patients on Day 14, with a highly significant association between them (p<0.001). Among 316 patients, only 41 (4.4%) of all BRV-treated patients experienced adverse events; Of these 41 patients, 17 (41.7%) reported dizziness and 14(34.2%) reported behavioral issues. Epileptic patients receiving BRV demonstrated a substantial reduction of greater than 50% seizure episodes at the end of follow-up visits. Moreover, BRV exhibited fewer adverse effects in individuals with epilepsy.

Brivaracetam as add-on therapy in children with developmental epileptic encephalopathies: A study of 42 patients

ObjectiveHere we present a multicenter series of patients with developmental epileptic encephalopathies (DEE) who were treated with brivaracetam (BRV) as add-on therapy. MethodsMedical records of 42 patients with DEE treated with add-on BRV seen at four pediatric neurology centers in Argentina between January 2021 and July 2023 were retrospectively analyzed. ResultsWe included 42 patients (26 males, 16 females) with a mean age of 7 years (SD, ± 3.8; median, 9; range, 2–16). The children had different types of childhood-onset treatment-resistant DEEs and received BRV as add-on therapy for a mean period of 2 years (SD, ± 1.3 years; median, 1.5 years; range, 0.5–3 years). Thirty-three patients received levetiracetam (LEV) before the introduction of BRV. In nine patients, BRV was started without prior LEV because of behavioral disturbances. Three patients (9.5 %) became seizure free and 26/42 patients (62.1 %) had a greater than 50 % decrease in seizures after a mean follow-up of 21 months. Ten patients (23.8 %) had a 25–50 % seizure reduction, while seizure frequency remained unchanged in two (4.7 %) and increased in one patient (2.4 %). The interictal EEG abnormalities improved in all the responders. Adverse effects, consisting of drowsiness, irritability, and decreased appetite, were observed in seven patients (16.6 %), but did not lead to treatment discontinuation. ConclusionBrivaracetam was found to be effective, safe, and well tolerated in children with DEE. In patients on LEV with behavioral disturbances, BRV may be tried. BRV may also be given without a previous trial with LEV in patients with behavioral problems.

Real-Life Effectiveness and Tolerability of Brivaracetam in Focal to Bilateral and Primary Generalized Tonic-Clonic Seizures

Purpose. Brivaracetam (BRV), an antiseizure medication indicated for focal-onset seizures, has shown efficacy in the treatment of focal to bilateral tonic-clonic seizures (FBTCS). We aimed to determine the effectiveness and safety of BRV in patients with FBTCS and generalized tonic-clonic seizures (GTCS). Methods. We performed a multicenter, retrospective, longitudinal study in adult patients with epilepsy who experienced at least one FBTCS or GTCS before starting BRV (baseline visit). Data were collected from consecutive outpatient visits over a 4-year period. All patients had been followed for at least 3 months before the baseline visit and completed a minimum follow-up of 3 months after starting BRV. Response (≥50% reduction in FBTCS/GTCS frequency) and retention rates, as well as seizure freedom and presence of adverse events at 3, 6, and 12 months, were recorded as outcome measures. Results. 114 patients were included (mean age 36.3 ± 18.0 years, 52% male, 36.6% genetic generalized epilepsy); 94 had a 12-month follow-up period. At 12 months’ follow-up, the response rate was 83%, and 73.4% of patients were FBTCS/GTCS-free. Retention was 79% at 12 months. Adverse events occurred in 29.8% of patients, the most common being drowsiness (14.9%). No significant differences were found in response rates between FBTCS and GTCS. Drug resistance was independently associated with lower response and seizure freedom rates at follow-up. The absence of a titration period predicted seizure freedom and response at 3 months. Conclusions. BRV is an effective and well-tolerated treatment in patients with focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures.

The real-world effectiveness of intravenous brivaracetam as a second-line treatment in status epilepticus

PurposeStatus epilepticus (SE) is defined by abnormally prolonged seizures that may lead to brain damage and death. Our aim was to evaluate the efficacy and tolerability (effectiveness) of intravenous brivaracetam (BRV) as a second-line treatment. Methods: Twenty-one patients (median age 68 years ± 17.28) were prospectively recruited between June 2019 and December 2022. Patients were treated with BRV (50–200 mg) as a second-line add-on therapy for SE. We evaluated the response of SE to the administration of BRV in terms of SE termination and recurrence of epileptic seizures at 6, 12, and 24 h, also monitoring safety. The first-line therapy was represented by intravenous benzodiazepines (mainly diazepam). Results: Almost a quarter of patients had generalized seizures, whereas the vast majority (76.2%) presented focal seizures. In 52.4% of patients, the underlying cause was cerebrovascular. Fourteen (66.7%) patients displayed a good early response in the subsequent 6 h. At 12 and 24 h, 8 (38%) and 11 (52.4%) patients, respectively, did not present seizures. Conclusion: The present study highlights the potential of BRV when used as an early add-on therapy in SE, further confirming its good safety profile.

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy

AbstractObjectiveThis study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add‐On First Italian Network Study (BRIVAFIRST).MethodsBRIVAFIRST was a 12‐month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as &lt;5, 5–20, and &gt;20 seizures per month, and the number of prior antiseizure medications (ASMs) as &lt;5 and ≥6.ResultsA total of 994 participants were included. During the 1‐year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of &lt;5, 5–20, and &gt;20 seizures per month (p &lt; .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p &lt; .001). SSR was reached by 51.2% and 26.5% participants with a history of 1–5 and ≥6 ASMs (p &lt; .001); the corresponding rates of SSF were 24.7% and 4.5% (p &lt; .001). Treatment discontinuation due to lack of efficacy was more common in participants with &gt;20 seizures compared to those with &lt;5 seizures per month (25.8% vs. 9.3%, p &lt; .001), and in participants with history of ≥6 prior ASMs compared to those with history of 1–5 ASMs (19.6% vs. 12.2%, p = .002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs.SignificanceThe baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.

Long-term safety and efficacy of adjunctive brivaracetam in pediatric patients with epilepsy: An open-label, follow-up trial.

To evaluate the long-term safety, tolerability, and efficacy of adjunctive brivaracetam (BRV) treatment in pediatric patients with epilepsy. Phase 3, open-label, multicenter, long-term follow-up trial (N01266; NCT01364597; patients aged 1 month to <17 years at core trial entry; direct enrollers aged 4 to <17 years) treated with BRV. Outcomes included treatment-emergent adverse events (TEAEs), behavior assessments (Achenbach Child Behavior Checklist [CBCL]; Behavior Rating Inventory of Executive Function [BRIEF-P/BRIEF]), and efficacy outcomes (percent change in focal seizure frequency, 50% responder rate for all seizure types for patient subgroups <2 years and ≥2 years of age using daily record card data). Of 257 patients with ≥1 dose of BRV (141 [54.9%] male; mean age: 8.0 years [SD 4.5]), 36 patients were <2 years of age, and 72.0% of patients had a history of focal seizures. Mean BRV exposure was 3.2 patient-years. At least one TEAE occurred in 93.4% patients and 32.3% had serious TEAEs. Seven patients died during the trial; no deaths were considered treatment related. Patients ≥2 years of age had a median decrease in 28-day adjusted focal seizure frequency of 62.9%, and 50.9% had a ≥50% response in all seizures. Patients <2 years of age had a median decrease in 28-day adjusted focal seizure frequency of 96.9%, and 68.2% had a ≥50% response in all seizures. Kaplan-Meier estimated treatment retention was 72.7%, 64.5%, 57.8%, 53.3%, 50.1%, and 44.8% at 1, 2, 3, 4, 5, and 6 years, respectively. Mean changes (baseline to last evaluation) for all Achenbach CBCL and BRIEF-P/BRIEF subscale scores were negative, reflecting stability/slight improvement. Long-term adjunctive BRV treatment was generally well tolerated, efficacious in reducing seizure frequency, and had high retention rates, with generally stable cognitive/behavioral scores in pediatric patients with epilepsy.

Effectiveness and Tolerability of 12-Month Brivaracetam in the Real World: EXPERIENCE, an International Pooled Analysis of Individual Patient Records.

Real-world evidence studies of brivaracetam (BRV) have been restricted in scope, location, and patient numbers. The objective of this pooled analysis was to assess effectiveness and tolerability of brivaracetam (BRV) in routine practice in a large international population. EXPERIENCE/EPD332 was a pooled analysis of individual patient records from multiple independent non-interventional studies of patients with epilepsy initiating BRV in Australia, Europe, and the United States. Eligible study cohorts were identified via a literature review and engagement with country lead investigators, clinical experts, and local UCB Pharma scientific/medical teams. Included patients initiated BRV no earlier than January 2016 and no later than December 2019, and had ≥6 months of follow-up data. The databases for each cohort were reformatted and standardised to ensure information collected was consistent. Outcomes included ≥50% reduction from baseline in seizure frequency, seizure freedom (no seizures within 3 months before timepoint), continuous seizure freedom (no seizures from baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were considered non-responders/not seizure free. Analyses were performed for all adult patients (≥16 years), and for subgroups by seizure type recorded at baseline; by number of prior antiseizure medications (ASMs) at index; by use of BRV as monotherapy versus polytherapy at index; for patients who switched from levetiracetam to BRV versus patients who switched from other ASMs to BRV; and for patients with focal-onset seizures and a BRV dose of ≤200mg/day used as add-on at index. Analysis populations included the full analysis set (FAS; all patients who received at least one BRV dose and had seizure type and age documented at baseline) and the modified FAS (all FAS patients who had at least one seizure recorded during baseline). The FAS was used for all outcomes other than ≥50% seizure reduction. All outcomes were summarised using descriptive statistics. Analyses included 1644 adults. At baseline, 72.0% were 16-49 years of age and 92.2% had focal-onset seizures. Patients had a median (Q1, Q3) of 5.0 (2.0, 8.0) prior antiseizure medications at index. At 3, 6, and 12 months, respectively, ≥50% seizure reduction was achieved by 32.1% (n=619), 36.7% (n=867), and 36.9% (n=822) of patients; seizure freedom rates were 22.4% (n=923), 17.9% (n=1165), and 14.9% (n=1111); and continuous seizure freedom rates were 22.4% (n=923), 15.7% (n=1165), and 11.7% (n=1111). During the whole study follow-up, 551/1639 (33.6%) patients discontinued BRV. TEAEs since prior visit were reported in 25.6% (n=1542), 14.2% (n=1376), and 9.3% (n=1232) of patients at 3, 6, and 12 months, respectively. This pooled analysis using data from a variety of real-world settings suggests BRV is effective and well tolerated in routine clinical practice in a highly drug-resistant patient population.

Rapid switching from levetiracetam to brivaracetam in pharmaco-resistant epilepsy in people with and without intellectual disabilities: a naturalistic case control study.

Approximately one quarter of people with an intellectual disability (PwID) have epilepsy of whom nearly three-quarters are pharmaco-resistant. There are higher reported neuropsychiatric side-effects to anti-seizure medication (ASM) in this group. Levetiracetam (LEV) is a first-line ASM with a stronger association with neuropsychiatric symptoms for PwID than other ASMs. Brivaracetam (BRV) is a newer ASM. Recent studies suggest a beneficial effect of swapping people who experience neuropsychiatric events with LEV to BRV. However, there is limited evidence of this for PwID. This evaluation analyses real world outcomes of LEV to BRV swap for PwID compared to those without ID. We performed a multicentre, retrospective review of clinical records. Demographic, clinical characteristics and reported adverse events of patients switched from LEV to BRV (2016-2020) were recorded at 3months pre and 6- and 12-month post-BRV initiation. Outcomes were compared between PwID and those without and summarised using cross-tabulations and logistic regression models. A Bonferroni correction was applied. Of 77 participants, 46 had ID and 52% had a past psychiatric illness. 71% participants switched overnight from LEV to BRV. Seizure reduction of > 50% was seen in 40% patients. Psychiatric illness history was predictive of having neuropsychiatric side-effects with LEV but not BRV (p = 0.001). There was no significant difference for any primary outcomes between PwID versus without ID. Switching from LEV to BRV appears as well tolerated and efficacious in PwID as those without ID with over 90% still on BRV after 12months.

4-AP challenge reveals that early intervention with brivaracetam prevents posttraumatic epileptogenesis in rats

PurposeThere are currently no clinical treatments to prevent posttraumatic epilepsy (PTE). Recently, our group has shown that administration of levetiracetam (LEV) or brivaracetam (BRV) shortly after cortical neurotrauma prevents the development of epileptiform activity in rats, as measured ex vivo in neocortical slices. Due to the low incidence of spontaneous seizures in rodent-based models of traumatic brain injury (TBI), chemoconvulsants have been used to test injured animals for seizure susceptibility. We used a low dose of the voltage-gated potassium channel blocker 4-aminopyridine (4-AP) to evaluate posttraumatic epileptogenesis after controlled cortical impact (CCI) injury. We then used this assessment to further investigate the efficacy of BRV as an antiepileptogenic treatment. MethodsSprague-Dawley rats aged P24–35 were subjected to severe CCI injury. Following trauma, one group received BRV-21 mg/kg (IP) at 0–2 min after injury and the other BRV-100 mg/kg (IP) at 30 min after injury. Four to eight weeks after injury, animals were given a single, low dose of 4-AP (3.0–3.5 mg/kg, IP) and then monitored up to 90 min for stage 4/5 seizures. ResultsThe chemoconvulsant challenge revealed that within four to eight weeks, CCI injury led to a two-fold increase in percentage of rats with 4-AP induced stage 4–5 seizures relative to sham-injured controls. Administration of a single dose of BRV within 30 min after trauma significantly reduced injury-induced seizure susceptibility, bringing the proportion of CCI-rats that exhibited evoked seizures down to control levels. ConclusionsThis study is the first to use a low dose of 4-AP as a chemoconvulsant challenge to test epileptogenicity within the first two months after CCI injury in rats. Our findings show that a single dose of BRV administered within 30 min after TBI prevents injury-induced increases in seizure susceptibility. This supports our hypothesis that early intervention with BRV may prevent PTE.

A Novel RP-Chiral Separation Technique for the Quantification of Brivaracetam and its process Related Isomeric Impurities using High Performance Liquid Chromatography

Reverse‐phase high‐performance liquid chromatography method has been developed for the determination of brivaracetam (BRV) with its stereoisomeric impurities (BRV-SS), (BRV-RR) and (BRV- RS). Brivaracetam with its impurities has been eluted with good resolution using the chiral column, chiralpakIG (250 × 4.6mm, 5µ) column at the detection wavelength of 210nm with the flow rate of 0.50ml/minute. The separation was achieved with the mobile phase consisted of methanol: acetonitrile and trifluoroacetic acid in the volume ratio of 90:10:0.1. The column temperature was maintained at 30°C and detection wavelength was maintained at 210 nm. Brivaracetum (BRV), and stereoisomeric impurities, BRV-SS, BRV-RR and BRV-RS, were eluted at 13.829, 11.810, 10.448 and 9.449 min, respectively. The method showed adequate specificity, sensitivity, linearity, accuracy, precision, and robustness inline to ICH tripartite guidelines. The limit of detections were 0.2 μg/mL for BRV-SS and BRV-RR, for BRV-RS it was found 0.1μg/mL.The limit of quantification limits were 0.5μg/mL for BRV-SS, BRV-RR and for BRV-RS as well.The developed method was found to be linear over the concentration range of 0.5-20µg/mL for BRV-RS, for BRV-RR and BRV-RS it was 0.5-3µg/mLfor stereoisomeric impurities with a correlation coefficient of 0.999. The developed method was found precise (%RSD = 0.5%, 0.6% and 0.5% for BRV-SS, BRV-RR and BRV-RS,) accurate (with 96%–107% recovery) and found robust. The validation parameters of the developed method were within the limits as per the regulation of ICH Q2(R1) guidelines. Therefore, in this present method a good separation was achieved specifically for the identification of brivaracetam and its processed related stereoisomeric impurities using high performance liquid chromatography and found suitable for the quantification of stereoisomeric impurities of brivaracetam in bulk scale as well.