Abstracts

Rationale:
Cenobamate is an antiseizure medication (ASM) approved in the US for treatment of focal seizures. Adjunctive cenobamate may reduce plasma levels of concomitant lamotrigine and carbamazepine, thus dose adjustments to these drugs may be considered. Here we report post-hoc analysis of how dose adjustments to lamotrigine and carbamazepine impacted efficacy and tolerability in 10 US study sites in an ongoing, global, phase 3 study (N=1347 enrolled) of cenobamate.
Method:
Patients with uncontrolled focal seizures on stable doses of 1-3 ASMs were enrolled. Increasing daily doses of cenobamate were administered (12.5, 25, 50, 100, 150, and 200 mg/day) at 2-week intervals. Increases to 400 mg/day by 50-mg/day increments biweekly were permitted. Adjustments to concomitant ASMs were allowed. Results249 patients had available data; 183 (73.5%) remained on cenobamate. The Table shows data for patients on concomitant lamotrigine or carbamazepine at baseline. Of patients who continued cenobamate, 28/52 (53.8%) lamotrigine and 10/14 (71.4%) carbamazepine patients had their concomitant ASM dose reduced. Dose reductions for those who continued vs discontinued cenobamate suggest that greater dose reductions of either concomitant ASM led to more patients remaining on cenobamate (Figure). Of patients who continued cenobamate, lamotrigine and carbamazepine were discontinued completely in n=8 (15.4%) and n=4 (28.6%) patients. Dose reductions of lamotrigine and carbamazepine occurred most often due to adverse events (AEs) of dizziness, diplopia, and sleepiness. 62/183 (33.9%) of patients on cenobamate were seizure-free for ≥12 months at the last 3-month visit and 17/62 (27.4%) were on concomitant lamotrigine. This was similar to the percentages of patients on lamotrigine from all evaluable patients (69/249; 27.7%), those continuing cenobamate (regardless of seizure freedom; 52/183; 28.4%), and those who discontinued cenobamate (17/66; 25.8%). For concomitant carbamazepine, there were slightly fewer patients in the seizure-free group at 4.8% (3/62) vs 8.8% (22/249) of all evaluable, 7.7% (14/183) of continued cenobamate patients, and 12.1% (8/66) of those who discontinued cenobamate.
Conclusion:
In this post-hoc analysis, greater dose reductions of lamotrigine and carbamazepine led to more patients remaining on cenobamate. Based on retention rates and few complaints of seizure worsening, efficacy did not seem to be significantly compromised and AEs decreased with reductions in these concomitant ASMs. Because the proportion of patients on these concomitant drugs did not differ in seizure-free patients, it appears that efficacy seen with cenobamate may be due to cenobamate itself and not due to a combination effect. Despite data indicating increasing doses of concomitant lamotrigine and carbamazepine should be considered due to possible PK interactions with cenobamate, doses of these ASMs were reduced due to pharmacodynamic considerations and negative changes in efficacy were infrequent.
Funding:
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Funding:
: SK Life Science, Inc.