A retrospective non‐interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam

Elakkary, Sally; Hagemann, Anne; Klimpel, Dennis; Bien, Christian G.; Brandt, Christian

doi:10.1111/epi.17515

Cited by 17 publications

(8 citation statements)

References 16 publications

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“…This is consistent with a recent study showing that concomitant CNB and clobazam can lead to a substantial increase in serum concentrations of N‐desmethylclobazam. This may lead to both a positive therapeutic effect and unwanted AEs 33 . Therefore, there is a rationale for considering a low dosage of clobazam when used in combination with CNB (5‐10 mg).…”

Section: Discussionmentioning

confidence: 99%

Real‐world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program

Villanueva,

Santos‐Carrasco,

Cabezudo‐García

et al. 2023

Epilepsia Open

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ObjectiveThis study investigated early, real‐world outcomes with cenobamate (CNB) in a large series of patients with highly drug‐resistant epilepsy within a Spanish Expanded Access Program (EAP).MethodThis was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3‐, 6‐, and 12‐month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.ResultsThe study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness.SignificanceIn this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild‐to‐moderate, and few led to discontinuation.

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Section: Discussionmentioning

confidence: 99%

Real‐world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program

Villanueva,

Santos‐Carrasco,

Cabezudo‐García

et al. 2023

Epilepsia Open

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“…Such increase of N-CLB was associated with somnolence in our patients. Notably, a variable (between 145% and 1852%) increase in N-CLB serum concentration has been reported in a recent study (Elakkary et al, 2023). The authors suggest a potential role of the pharmacogenetics of the hepatic enzyme CYP2C19 to explain this high rate of variability and report fatigue as a direct consequence of N-CLB increase (Elakkary et al, 2023).…”

Section: Discussionmentioning

confidence: 86%

Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?

Pietrafusa,

Falcicchio,

Russo

et al. 2023

Front. Pharmacol.

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Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs.Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6 months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100–400 mg/day (65 measures).Results: we enrolled 54 patients with a median age of 27.9 years. The mean follow-up was 10.7 months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p < 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(μg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(μg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = −0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p < 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6 months evaluation of 4.53 (p = 0.03).Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as “victim” and as “perpetrator” of drug-drug interactions.

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“…In the case of GABAergic drugs, special attention should be given to benzodiazepines and benzodiazepine‐derived drugs, and to CLB in particular due to the pharmacokinetic and pharmacodynamic interactions reported with cenobamate. 15 , 26 , 27 …”

Section: Resultsmentioning

confidence: 99%

“…In the case of GABAergic drugs, special attention should be given to benzodiazepines and benzodiazepine-derived drugs, and to CLB in particular due to the pharmacokinetic and pharmacodynamic interactions reported with cenobamate. 15,26,27 In patients taking clobazam ≥20 mg/day, proactive dose reduction should be considered when the administered dose of cenobamate reaches 50-100 mg/day to avoid the risk of drowsiness (Figure 2). However, they recommend not completely withdrawing clobazam, as in some patients, a low dose of clobazam (5-10 mg/day) in combination with cenobamate could exert a beneficial effect on seizure control.…”

Section: Gabaergicsmentioning

confidence: 99%

Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug‐resistant focal seizures

Carreño,

Gil‐Nagel,

Serratosa

et al. 2024

Epilepsia Open

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ObjectiveCenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug‐related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug‐resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate.MethodsA three‐stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration.ResultsThe expert panel agreed that tailored titration and close follow‐up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period.SignificanceCenobamate is an effective ASM with a dose‐dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co‐medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co‐medication in cenobamate‐treated patients with DRE and a high drug load.Plain Language SummaryPatients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug‐resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate.

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A retrospective non‐interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam

Cited by 17 publications

References 16 publications

Real‐world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program

Real‐world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program

Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?

Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug‐resistant focal seizures

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