Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response

Aícua‐Rapún, Irene; André, Pascal; Rossetti, Andrea O.; Décosterd, Laurent A.; Buclin, Thierry; Nový, Jan

doi:10.1016/j.eplepsyres.2018.12.001

Cited by 41 publications

(34 citation statements)

References 19 publications

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“…At >50%, the effectiveness rate is similar to that published by Kalss et al (seven patients; 57%) and Aicua‐Rapun et al (14 patients; 50%); compared with the Strzelczyk cohort (11 patients; 27%), the response rate of our sample is higher, although in his series only refractory and superrefractory cases were reported and BRV was administered later.…”

Section: Discussionsupporting

confidence: 89%

“…Effectiveness in SE in the context of IGE was also found; of the five patients with previous IGE diagnosis, three had a fast clinical and EEG response, with this occurring within 10‐20 minutes in two of them. The only published information on BRV used for SE in IGE patients is the two cases reported by Strzelczyk et al of SE with absences, which had no response . In our cases, the three IGE responder patients were already on treatment with BRV, the cause of their SE was abrupt drug withdrawal (forgot medication), and all three had a predominantly myoclonic component (two previous diagnoses of JME and one of Jeavons syndrome); the two nonresponders were SE with absences with no myoclonic component.…”

Section: Discussionmentioning

confidence: 55%

“…Three series of patients with SE treated with BRV have been published to date. The Strzelczyk et al series consisted of 11 patients with refractory SE, with a response rate of 27%; Kalss et al reported a higher effectiveness rate of 57% in seven patients who received BRV in an earlier phase; and more recently, Aicua‐Rapun et al reported a series of 14 patients with an SE control rate of 50% . In the context of idiopathic generalized epilepsy (IGE), only two cases of SE have been published, both unresponsive to BRV …”

Section: Introductionmentioning

confidence: 99%

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Use of intravenous brivaracetam in status epilepticus: A multicenter registry

et al. 2019

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Objective 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. Methods 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. Results Forty‐three patients were registered. The mean age was 56 ± 23.1 years, 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 100 mg (range = 50‐400), and the weight‐adjusted dose was 1.8 mg/kg (range = 0.4‐7.3). BRV was effective in 54% (n = 23), and a response was observed in <6 hours 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 (300 mg vs 100 mg, P = 0.008) and the weight‐adjusted dose (3.85 mg vs 1.43 mg, P = 0.006) were significantly higher. The receiver operating characteristic curve showed that the best cutoff point for a faster response was 1.82 mg/kg. Significance 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 (>1.82 mg/kg).

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

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Use of intravenous brivaracetam in status epilepticus: A multicenter registry

et al. 2019

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“…Despite neither BRV nor LEV being indicated for SE, recent studies have suggested that SE patients can be treated with BRV, with loading doses similar to those in this study . A further recent study has reported that a human dose of at least 2 mg/kg and up to 5 mg/kg is necessary for efficacy in SE, suggesting that doses slightly above 100 mg BRV intravenously could be in the efficacious range . The tracer displacement half‐time is an underestimation of the drug brain entry half‐time, because of the time taken for tracer clearance from tissue.…”

Section: Discussionmentioning

confidence: 57%

A single‐center, open‐label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers

et al. 2019

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Summary Objective Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11C‐UCB‐J (; ). Methods Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50‐200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice‐daily oral dosing of BRV (50‐100 mg) and 4 hours postdose of LEV (250‐600 mg). Half‐time of 11C‐UCB‐J signal change was computed from displacement measurements. Half‐saturation concentrations (IC50) were determined from calculated SO. Results Observed tracer displacement half‐times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half‐times were 8 minutes shorter. The SO was 66%‐70% for 100 mg intravenous BRV, 84%‐85% for 200 mg intravenous BRV, and 78%‐84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 μg/mL) was 8.7‐fold lower than of LEV (4.02 μg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%‐87% (peak) and 76%‐82% (trough). Significance BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.

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“…(mRS) scores at admission and discharge, and in responders and nonresponders to topiramate (TPM) [41][42][43] Two recent case series reported on the use of oral perampanel in patients with various stages of SE, reporting response rates between 17% 44 and 37%. 45 Use of oral oxcarbazepine in SE was reported in 13 patients with a median treatment latency of 81 hours.…”

Section: F I G U R E 2 Modified Rankin Scalementioning

confidence: 99%

Treatment of refractory and superrefractory status epilepticus with topiramate: A cohort study of 106 patients and a review of the literature

et al. 2019

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Objective: Novel treatments are needed to control treatment-resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE). Methods: A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation. Results: In total, TPM was used in 106 of 854 patients having a mean age of 67.4 ± 18.1 years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5 days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100 mg/d, which was uptitrated to a median maintenance dose of 400 mg/d. Treatment with TPM was continued for a median time of 12 days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment-emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty-four of these patients received a combination of TPM and valproate and/or phenobarbital.The intrahospital mortality rate was 22.6% (n = 24). Significance: The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than 8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.

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Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response

Cited by 41 publications

References 19 publications

Use of intravenous brivaracetam in status epilepticus: A multicenter registry

Use of intravenous brivaracetam in status epilepticus: A multicenter registry

A single‐center, open‐label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers

Treatment of refractory and superrefractory status epilepticus with topiramate: A cohort study of 106 patients and a review of the literature

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