SPECIAL REPORT
Mechanism of action
Efficacy and safety studies
Use of adjunctive cenobamate in practice
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The estimated prevalence of epilepsy in Canada is about 1% – an increase of 22% over the past decade (www.canada.ca/en/public-health/services/publications/diseases-conditions/epilepsy.html). Over 30 antiseizure medications (ASM) are currently available and have been generally effective in reducing seizure frequency. A 30-year observational study (N=1795) found that 63.7% of patients were seizure-free at one year, with most achieving seizure control with the first or second medication (Chen et al. JAMA Neurol 2018;75:279-286). But for treatment-refractory patients, few attained optimal seizure with subsequent treatments. Thus, drug-resistant epilepsy remains a key challenge in clinical management and over 200 novel ASMs are currently in development (Klein et al. Nat Rev Drug Discov 2024;23:682-708). Of the newer agents, considerable success has been seen with cenobamate, a dual-action ASM approved in Canada last year as adjunctive therapy for focal seizures.
Mechanism of action
ASMs may be categorized according to four mechanisms of action: modulators of voltage-gated channels (sodium, calcium, potassium); drugs that target gamma-aminobutyric acid (GABA) via GABAA receptors, GABA transporter 1, glutamic acid decarboxylase or GABA aminotransferase; inhibitors of synaptic excitation via ionotropic glutamate receptors (e.g. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptors); and modulators of neurotransmitter release (Klein 2024).
The monocarbamate cenobamate appears to act primarily via two mechanisms: blockade of persistent Na+ channels (Nakamura et al. Eur J Pharmacol 2019;855:175-182); and modulation of GABA-induced currents mediated by GABAA receptors (Sharma et al. Eur J Pharmacol 2020:879:173117). Drug effects are more potent on persistent versus transient Na+ channels, which may permit suppression of sustained depolarizations without affecting low-frequency firing or single action potentials. Cenobamate also enhances the inactivated state of voltage-gated Na+ channel (Loscher et al. Epilepsia 2021;62:596-614).
Efficacy and safety studies
The efficacy of adjunctive cenobamate was investigated in adult patients with drug-resistant focal epilepsy in the C013 and C017 trials. In C013 (N=222), a six-week titration phase was followed by a six-week maintenance phase (Chung et al. Neurology 2020;94:e2311-e2322). The cenobamate dose was titrated to 200 mg/day in 66.7%, 150 mg/day in 24.5% and 50-100 mg/day in 8.9%. In the cenobamate group, median seizure frequency over 28 days was reduced from 7.5 to 3.8 (55.6% reduction) compared to a reduction of 5.5 to 5.0 for placebo (21.5%% reduction). The ≥50% responder rate was significantly greater with cenobamate versus placebo (50.4% vs. 22.2%). A total of 28.3% of cenobamate-treated patients were seizure-free during the maintenance phase compared to 8.8% in the placebo group.
The C017 trial randomized patients with uncontrolled focal seizures (N=437) to one of three doses of adjunctive cenobamate (100 mg/day, 200 mg/day, 400 mg/day) or placebo (Krauss et al. Lancet Neurol 2020;19:38-48). An eight-week assessment phase was followed by a six-week titration phase and a 12-week maintenance phase. The median percentage change from baseline in seizure frequency was -55.0% with cenobamate 200 mg/day or 400 mg/day, -35.5% with cenobamate 100 mg/day versus -24.0% with placebo. The ≥50% responder rate was greater with cenobamate 400 mg, 200 mg and 100 mg versus placebo (64%, 56% and 40% vs. 25%). The seizure-free rates during the maintenance phase were 21.1%, 11.2% and 3.9% in the cenobamate groups compared to 1% in the placebo group.
The most common adverse effects in the two trials were somnolence (24.7%), dizziness (23.3%), fatigue (16.1%), and headache (11.3%). A similar adverse-effect profile was reported in a phase III safety study (N=1347) (Sperling et al. Epilepsia 2020;61:1099-1108). The rate of serious adverse events was 8.1%; events included seizure, epilepsy, pneumonia, falling and dizziness. Three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) were reported in early clinical testing. No cases of DRESS occurred in the phase III study, which was attributed to a lower starting dose (12.5 mg/day) and the titration schedule (increased to 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg/day in two-week increments).
The retention rate for cenobamate-treated patients in the phase III study was >80% at six months. A recent real-world observational study (N=231) reported a higher one-year retention rate with cenobamate (92.0%) than with lacosamide (80.1%), levetiracetam (73.3%), valproate (68.2%) or topiramate (62.5%) (Winter et al. CNS Drugs 2024;38:733-742).
Use of adjunctive cenobamate in practice
The starting dose of cenobamate is 12.5 mg once-daily for two weeks, titrated to 25 mg/day in weeks 3-4, 50 mg/day in weeks 5-6, 100 mg/day in weeks 7-8, 150 mg/day in weeks 9-10, and to the usual maintenance dose of 200 mg/day thereafter. The dose may be increased in 50 mg-increments every two weeks to a maximum daily dose of 400 mg, if required.
As cenobamate is added to the ASM regimen, the dosing of concomitant ASMs should generally be reduced, according to consensus recommendations (Smith et al. Neurol Ther 2022;11:1705-1720). For example, for patients receiving clobazam 30-40 mg/day, the clobazam dose should be reduced 5-10 mg/day at cenobamate initiation, 5-10 mg/day at cenobamate 50 mg/day and 5-10 mg/day at cenobamate 100 mg/day. For clobazam >40 mg/day, the dose should be reduced 10-20 mg/day at the start of cenobamate dosing and 10-20 mg/day at cenobamate 25 mg/day.
For lacosamide >400 mg/day, the dose should be reduced 100 mg/day at cenobamate 50 mg/day, with a further 100 mg/day reduction at cenobamate 100 mg/day.
In patients with phenytoin blood level >15 µg/mL, the dose should be reduced 100 mg/day at cenobamate 25 mg/day and another 100 mg/day at cenobamate 50 mg/day. For phenobarbital, the dose should be reduced 25% at cenobamate 50 mg/day; an earlier reduction is recommended if phenobarbital levels are >25 µg/mL. A pocket guide to adjunctive cenobamate dosing is available at www.ncbi.nlm.nih.gov/pmc/articles/PMC9588096/pdf/40120_2022_Article_400.pdf.
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