Abstracts

Rationale:
Patients with epilepsy are often on concomitant antiseizure medications (ASMs) that may have interactions affecting efficacy and tolerability. Cenobamate is an ASM approved in the US for treatment of uncontrolled focal seizures. Clobazam is metabolized by cytochrome isoenzyme CYP3A4 to its active metabolite N-desmethylclobazam, which is mainly metabolized by CYP2C19. Cenobamate inhibits CYP2C19 and may increase plasma levels of N-desmethylclobazam. Here we report post-hoc results on how dose adjustments to concomitant clobazam impacted efficacy and tolerability in patients from 10 US study sites in an ongoing, global, phase 3 study (N=1347 enrolled) of adjunctive cenobamate.
Method:
Patients with uncontrolled focal seizures taking 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.
Results:
Data from 249 patients were available; 183 were still receiving cenobamate (73.5% retention). Of 249 total patients, 40 were receiving concomitant clobazam at baseline. Mean clobazam dose in those who remained on cenobamate (n=31) decreased from 37.1 mg to 12.9 mg (initial to last dose), and 7/31 (22.6%) patients discontinued clobazam completely. In contrast, clobazam dose was decreased less (36.1 mg to 26.1 mg) in the 9 patients who discontinued cenobamate. Clobazam dose was decreased at a mean visit number of 8.4 (~week 12) in patients who continued cenobamate (n=26), with a mean cenobamate dose of 134.6 mg at the time of clobazam dose adjustment. Clobazam doses were decreased most often due to AEs such as tiredness/fatigue, sleepiness/drowsiness, and feeling overmedicated. 62/183 (33.9%) patients on cenobamate were seizure-free for ≥12 months and 7/62 (11.3%) were on concomitant clobazam. This proportion is no greater than the percentage of patients on clobazam from all evaluable patients (40/249; 16.1%), those continuing cenobamate (regardless of seizure freedom; 31/183; 16.9%), or those who discontinued cenobamate (9/66; 13.6%). In 7 cases, clobazam dosage was relatively higher (mean 32.9 mg/day; range 25-50 mg/day) and tapered to 0. Seizures reoccurred or worsened in these 7 patients and clobazam was resumed at relatively low doses (2.5-10 mg) to improve seizure control.
Conclusion:
In this post-hoc analysis of a phase 3 study of cenobamate, patients who remained on cenobamate had greater dose reductions in concomitant clobazam vs those who discontinued cenobamate. Due to interactions with cenobamate, particularly through CYP2C19, concomitant clobazam dose reduction (especially for higher clobazam doses) should be considered in patients taking adjunctive cenobamate to avoid possible tolerability issues, particularly drowsiness. Future studies should examine the combination of cenobamate and clobazam in patients who continue to have seizures on each of these drugs alone.
Funding:
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Funding:
: SK Life Science, Inc.