2024 American Academy of Neurology Abstract Website

Objective:

To examine post-hoc how and when investigators adjusted concomitant antiseizure medications (ASMs) during a phase 3 safety study of adjunctive cenobamate (N=1340).

Background:

A post-hoc analysis of a subset (n=240) of the phase 3 study indicated that reducing doses of concomitant ASMs led to better cenobamate retention (Rosenfeld 2021 Epilepsia).

Design/Methods:

Patients with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Increasing doses of cenobamate (12.5, 25, 50, 100, 150, and 200 mg/day) were administered biweekly; additional increases to 400 mg/day in biweekly 50-mg/day increments were permitted. Dose reductions of concomitant clobazam, phenytoin, phenobarbital, carbamazepine, lamotrigine, lacosamide, and levetiracetam were examined.

Results:

For CYP2C19 substrates clobazam, phenytoin, and phenobarbital, pharmacokinetic interactions resulted in increased plasma exposure and early dose reductions. By Visit 14 (Study Week 52), mean decrease in total clobazam dose was 30.9%; as investigators gained experience, dose reductions were made earlier and more proactively. Potential pharmacokinetic interactions between cenobamate, carbamazepine, and lamotrigine may cause decreased plasma exposure to those ASMs. Most concomitant carbamazepine and lamotrigine dosages were lowered or unchanged; these dose decreases may have led to better cenobamate tolerability, allowing for successful cenobamate up-titration. Although cenobamate does not cause changes to lacosamide plasma exposure, pharmacodynamic interactions likely resulted in investigators making dose reductions to improve tolerability as the cenobamate dose was increased; by Visit 14 the total daily lacosamide dose was decreased by 21.7%. Maintenance-phase dose decreases of levetiracetam (no known pharmacokinetic/pharmacodynamic interactions with cenobamate), were likely intended to reduce overall drug burden.

Conclusions:

These results support the concept that dosages of adjunctive ASMs (eg, clobazam, phenytoin, phenobarbital, lacosamide) should be adjusted early during cenobamate treatment. As investigators gained experience with cenobamate, earlier and larger dose reductions of concomitant ASMs were made, as reflected by current consensus recommendations (Smith 2022 Neurol Ther. 11(4):1705-20).