Πολυκεντρική μελέτη για τη χρήση της μπριβαρασετάμης σε ασθενείς με επιληψία

To evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs). Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 s) confirmed by video-electroencephalography, and inadequate seizure control with at least one ASM. A screening period (up to 36 h) was followed by a 48-h evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment-emergent adverse events (TEAEs). Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All six patients completed the evaluation period; two entered and completed the extension period. Overall (evaluation and extension periods), three patients received one dose of 0.5 mg/kg BRV and three received more than one dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n = 6). At 0.5-1, 2-4, and 8-12 h following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n = 5]), 0.50 mg/L (28.20% [n = 6]), and 0.34 mg/L (13.20% [n = 5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced four TEAEs, none of which were considered related to BRV. BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg b.i.d. BRV was well tolerated, with no drug-related TEAEs reported. Few drugs are available to treat seizures in newborn babies. Brivaracetam is approved to treat focal-onset seizures in children and adults in Europe (patients 2 years of age and older) and the United States (patients 1 month of age or older). In this study, six newborns with repeated seizures were treated with intravenous brivaracetam. The study doctors took samples of blood from the newborns and measured the levels of brivaracetam. The concentrations of brivaracetam in the newborns' blood plasma were consistent with data from studies in older children and in adults. No brivaracetam-related medical problems were reported.

IntroductionThe 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.MethodsThis 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 12 months. 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.ResultsA 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 6 months and 83.9% (26/31) at 12 months. 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 6 months 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 12 months were higher among people who switched from levetiracetam to BRV monotherapy.ConclusionBrivaracetam may be a valuable treatment of focal seizures in people who converted to monotherapy in a real-life setting.

Modelling life trajectories and mode choice using Bayesian belief networks

Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy—A monocenter survey

The study aimed to evaluate the clinical efficacy and safety of brivaracetam (BRV) as monotherapy or adjuvant therapy for adults with seizures. Observational studies of BRV were systematically searched. We estimated the pooled incidence of interests (responder rate, seizure-free rate, adverse effects (AEs), and withdrawal rate) with their corresponding 95% confidence intervals (CIs). Thirty-five studies, including 10,956 patients, were included. The 50% responder rates were 36% (95% CI: 0.26-0.47), 35% (95% CI: 0.21-0.49), and 40% (95% CI: 0.24-0.56), respectively, and the pooled seizure-free rates were 19.0% (95% CI: 0.17-0.25), 21.0% (95% CI: 0.15-0.27), and 23.3% (95% CI: 0.14-0.31), respectively, at 3, 6, and 12months of BRV treatment. Subgroup analysis showed that although previous levetiracetam (LEV) failure can affect the response to BRV, treatment with BRV could still be beneficial for these patients. Furthermore, a remarkable reduction in seizure frequency and lower AEs were found among patients who switched directly from LEV to BRV. In addition, BRV, used as the first add-on or monotherapy, displayed a high 50% responder rate and seizure-free rate. The pooled incidence of AEs at 3, 6, and 12months of BRV treatment were 39.0% (95% CI: 0.27-0.50), 29.0% (95% CI: 0.18-0.39), and 34.0% (95% CI: 0.25-0.44), respectively; the withdrawal rates due to AEs were 7.0% (95% CI: 0.03-0.10), 11.1% (95% CI: 0.05-0.17), and 10.0% (95% CI: 0.07-0.13) at the same follow-up point. Our meta-analysis has shown BRV to be effective and well-tolerated in both short-term and long-term usage when used as monotherapy or adjuvant therapy for adults with seizures in real-world settings. BRV may be a valuable treatment when used as monotherapy, as a first add-on, and in patients who switched directly from LEV or previously failed to respond to or tolerate LEV. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251085564.

Pharmacokinetic interaction of brivaracetam on other antiepileptic drugs in adults with focal seizures: Pooled analysis of data from randomized clinical trials

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.

Epilepsy is one of those primary illnesses that affect the brain, and the population is estimated to be around 50 million people. Objective: To evaluate the efficacy and safety of adjunctive Brivaracetam therapy in adult patients with epilepsy. Methods: This observational, non-interventional, single-center study assessed the use of adjunctive Brivaracetam (BRV) in patients aged ≥16 years over six months (October 2023–March 2024). Eligible participants had stable antiepileptic drug (AED) regimens for at least one month before BRV initiation. Demographic data, seizure type, frequency, and intensity were documented at baseline, 3 months, and 6 months. The primary endpoint was the change in seizure frequency. Secondary outcomes included ≥50% seizure reduction, seizure freedom, and adverse events. Data were analyzed using SPSS version 23.0. Results: A total of 168 patients (mean age: 25.1 ± 12.9 years) received adjunctive BRV therapy. Partial seizures and comorbid depression were the most common indications for BRV use. Mean seizure frequency decreased from 5.26 ± 0.29 at baseline to 2.41 ± 0.24 at 3 months. All patients achieved seizure freedom by 6 months. Reported adverse effects were generally mild: somnolence 12 (7%), headache 10 (6%), and dizziness 9 (5%). Conclusions: Adjunctive BRV therapy demonstrated significant efficacy in reducing seizure frequency and achieving seizure freedom, with a favourable safety profile. These findings support BRV as a promising treatment option for patients with epilepsy unresponsive to conventional AEDs.

The pharmacokinetics of brivaracetam (BRV), added to its effectiveness observed in animal models of status epilepticus (SE), makes this drug attractive for use in emergency situations. Our objective was to evaluate the use of intravenous BRV in a multicenter study. A retrospective multicenter registry of SE cases treated with BRV was created. These patients were evaluated between January and December 2018 at seven hospitals in Spain. Demographic variables, SE characteristics, concomitant drugs, loading doses, and response to treatment were collected. Forty-three patients were registered. The mean age was 56±23.1years, 51.2% were male, 29 had previous epilepsy, 24 (55.8%) had prominent motor symptoms, and 19 had nonconvulsive symptoms. Regarding the etiology, 19 (44.2%) were considered acute symptomatic, 16 (17.2%) remote symptomatic, four (9.3%) progressive symptomatic, and four (9.3%) cryptogenic. Regarding concomitant antiepileptic drugs (AEDs), 17 had previously received levetiracetam (LEV). In 14 patients, BRV was used early (first or second AED). The median loading dose was 100mg (range = 50-400), and the weight-adjusted dose was 1.8mg/kg (range = 0.4-7.3). BRV was effective in 54% (n=23), and a response was observed in <6hours in 13 patients. We observed a tendency for it to be more effective when administered earlier (P=0.09), but there were no differences regarding SE type and the concomitant use of LEV. In those with the fastest responses, we observed that both the total administered dose (300mg vs 100mg, P=0.008) and the weight-adjusted dose (3.85mg vs 1.43mg, P=0.006) were significantly higher. The receiver operating characteristic curve showed that the best cutoff point for a faster response was 1.82mg/kg. BRV is useful for the treatment of SE, even when patients are already being treated with LEV. The response rate seems higher when it is administered earlier and at higher doses (>1.82mg/kg).

Introduction: Our aim was to evaluate the clinical and electroencephalographic effects of brivaracetam (BRV) in patients with drug-resistant focal epilepsy. BRV is a new antiepileptic drug (AED) with a high affinity for vesicle protein 2A (SV2A) and recently approved as adjunctive therapy for focal onset seizures. Methods: In this observational study of six-month duration, BRV (50-200 mg) was administered to 76 patients with drug-resistant focal epilepsy, who were ≥16-year-old and who suffered from daily, weekly, monthly and yearly recurrent seizures. At baseline and after six months of follow-up, we performed a neurological visit, neuropsychological tests: Quality of life in epilepsy-31 (QOLIE31), Epworth Sleepiness Scale (ESS), Intrapersonal Emotional Quotient (IEQ) and an electroencephalogram (EEG; inspective and quantitative analysis). Twenty-four patients underwent an overnight switch from levetiracetam (LEV) to BRV. Results: Seizure frequency of the 54 patients remaining at six months was reduced >50% in 29.6% of cases (responders), <50% in 31.5% (non-responders 1), while it remained unchanged in 38.8% (non-responders 2). Twenty-nine percent of patients early discontinued BRV because of lack of efficacy or minor adverse effects (AEs) like irritability, asthenia or headache. Neuropsychological tests in 28 patients demonstrated a significant improvement in I-EPI scores (p=0.04). Comparable results have been found in the subgroup of patients who switched from LEV to BRV. The EEG quantitative analysis showed a significant reduction of alpha absolute power at six months (p=0.03). Theta band power resulted significantly superior in non-responders than in responders (p=0.03). Furthermore, the δ+θ/α+β index resulted more elevated in patients with AEs than in patients without. Conclusions: BRV showed discrete results in terms of efficacy, safety and tolerability, with a good behavioural profile. BRV reduces the power of the alpha band, in correlation with its sedative effects but not with its minor efficacy. Furthermore, the increase in theta band power can be considered as a predictor of scarce response to treatment, while an increase in the δ+θ/α+β index could be a possible predictor of AEs occurrence.

<b>Background:</b> Bradycardia and hypotension are complications commonly occurring during general anesthesia in small animals. Intraoperative hypotension has been found to be associated with adverse postoperative consequences. <br><b>Objectives: </b>The objectives of his study were first, to determine the incidence of bradycardia, hypotension, and bradycardia with hypotension in dogs undergoing general anesthesia, and second, to identify the risk factors associated with these three complications. The third objective was to evaluate the relationship between these three intraoperative complications and the recovery quality in these dogs.<br><b>Methods and Materials:</b> A retrospective cohort study was performed using anesthetic records from 250 dogs undergoing general anesthesia between May 23, 2018 and October 1, 2018 at the Purdue University Veterinary Teaching Hospital. Intraoperative bradycardia was defined as heart rate &lt; 60 beats/min for at least two consecutive readings at 5 minutes apart. Hypotension was defined as mean arterial pressure (MAP) &lt; 60 mmHg or a systolic arterial pressure (SAP) &lt; 80 mmHg for at least two consecutive readings. A univariate analysis followed by multiple logistic regression was performed to build the model for bradycardia, hypotension, and bradycardia with hypotension. The relationships between the three complications and the recovery quality were analyzed using the Pearson’s chi-square test.<br><b>Results:</b> The study found that out of the 250 dogs, 114 (45.6%) developed bradycardia, 113 (45.2%) developed hypotension, and 32 (12.8%) dogs developed bradycardia with hypotension. The use of dexmedetomidine-based tranquilizers/sedatives, longer duration of anesthesia, and subjection to orthopedic and neurologic surgical procedures were all identified as risk factors for the dogs to develop bradycardia. The use of acepromazine-based tranquilizers/sedatives, young and old age dogs, and dogs subjected to neurologic surgery were associated with the development of intraoperative hypotension. When the length of the anesthesia increased, the chance for developing bradycardia with hypotension increased. There was no significant association between these intraoperative complications and the recovery quality.<b><br></b><b>Conclusions:</b> We found a high incidence of bradycardia or hypotension while a much lower incidence of bradycardia with hypotension in the anesthetized dogs. The risk factors for bradycardia were the use of dexmedetomidine-based tranquilizers/sedatives, the longer duration of anesthesia, and the performance of orthopedic surgery and neurosurgery. The risk factors for hypotension included the use of acepromazine-based tranquilizers/sedatives, the older or younger age of dogs, and the performance of neurosurgery. The risk factor for bradycardia with hypotension was the longer duration of anesthesia. While these adverse events developed intraoperatively, we could not identify a direct influence of these complications on the recovery quality. <br>

Seizures are the most common neurological disorder in the clinical setting. Its etiology is multifactorial and is mainly divided into primary and secondary epilepsy. Secondary epilepsy can be caused by vascular events, inflammatory conditions (encephalitis), toxins, traumatic injuries, metabolic derangements, neoplasia, congenital and inherited (degenerative) disorders. Although primary (idiopathic) epilepsy was thought to be rare in cats, it is now established as a common cause. Seizures in cats appear with various clinical presentations including the typical generalized tonic-clonic, focal with or without secondary generalization seizures, or solely as behavioral changes. Type of seizures is not indicative of their etiology. Diagnostic investigation is crucial in order to establish final diagnosis and to determine the therapeutic plan. Diagnostics include physical and neurological examination with detailed history (drug or toxin exposure), routine hematology (CBC, biochemistry, urinalysis), specific laboratory tests if concurrent or metabolic disease are suspected, advanced diagnostic imaging (CT/MRI) whether intracranial disease is suspected and cerebrospinal fluid (CSF) analysis. Most commonly used antiepileptic drugs (AED) in cats are phenobarbital and levetiracetam. Bromide is contraindicated in cats due to severe respiratory disease caused as an adverse life-threatening reaction. Diazepam is an emergency AED used to eliminate cluster seizures or status epilepticus but it should be avoided as a long-term medication because it has been associated with fatal hepatotoxicity. Gabapentin in another potential antiepileptic drug however its long-term efficacy has to be evaluated. Prognosis depends on the underlying etiology and treatment response. In most cats quality of life is improved and (>50% reduction of seizures) regardless of etiology. The complete remission of seizures in cats is rare and most cats should be maintained on anti-epileptic therapy.

Brivaracetam add-on treatment in pediatric patients with severe drug-resistant epilepsy: Italian real-world evidence

The relative risk of cardiovascular death in patients with stage 5 chronic kidney disease (CKD) is 20 to 30 times higher when compared to the general population. Patients with CKD on hemodialysis (HD) tend to be sedentary, which in combination with other risk factors present in these patients increases cardiovascular complications and mortality. Objectives: Evaluate the effects of an intradialytic aerobic exercise program in patients with CKD performing HD on aerobic fitness and cardiovascular markers. Methods: Sixteen patients with CKD in HD were randomly stratified into two groups: exercise group (EG=9) and control group (CG=7). Collected demographic, clinical and biochemical data of the patients studied. Performed six-minute walk test (6MWT) to define target heart rate (HR) according to Oliveira et al. (2016) who proposed, in a population with heart failure, the formula: maximum heart rate (HR) at 6MWT plus 10% (MHR6MWT+10%) for submaximal aerobic training. Executed an individualized exercise program on a bicycle adapted during the dialysis sessions, three times / week for three months, lasting 45 min. Estimated the peak VO2 by the formula of Cahalin et al. (1996). Analyzed distance walked in 6MWT (DW6M), estimated VO2, CRP and BNP. Descriptive statistical analysis of the data was carried out. Results: After three months of exercise, the EG presented a significant increase in the DW6M, and their respective VO2 estimated: 462.3 ± 46.4 m (16.4 ± 2.8 ml.kg-1.min-1) for 497.3 ± 61.39 m (18.8 ± 2.9 ml.kg-1.min-1), respectively p=0.032 and p=0.014. There was no significant difference in CG with 427.1 ± 79.2 m (15.1 ± 1.7 ml.kg-1.min-1) for 400.2 ± 127.1 m (16.1 ± 3.2 ml.kg-1.min-1), respectively p=0.346 and p=0.399. Median BNP values in EG were reduced from 69.0 pg/mL to 33.7 pg/mL (p=0.021) and there was no significant change in the CRP values. There were no serious adverse events in EG. Conclusions: An intradialytic cycloergometric aerobic exercise program with intensity defined through the 6MWT was effective, safe and practical in chronic renal patients in HD. There were significant gains in aerobic capacity (estimated VO2 and DW6M) and a statistically significant reduction in BNP levels. There were no significant reductions in CRP levels in both groups

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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-024-02795-z.