New pharmacokinetic (PK) and pharmacodynamic (PD) data from a post-hoc analysis of the phase 3, open-label Study C021 (NCT02535091) showed that adjustments of concomitant antiseizure medications (ASM) should be performed earlier in the treatment with cenobamate (Xcopri; SK Life Science), an FDA-approved treatment for focal seizures.1 These findings support notion that dosages of adjunctive ASMs should be adjusted early in the treatment course with cenobamate, as it can lead to improved retention, and also inform recommendations for even earlier and larger reductions of these therapies in the clinical setting.2,3
These findings were presented at the 2023 American Epilepsy Society (AES) annual meeting, held December 1-5, in Orlando, Florida, by senior author William E. Rosenfeld, MD, FAAN, FAES, neurologist from the Comprehensive Epilepsy Care Center for Children and Adults, in St. Louis, Missouri, and colleagues. In the analysis, investigators examined the dose adjustments of concomitant ASMs of patients with uncontrolled focal seizures on cenobamate. In Study C021, increased doses of cenobamate (12.5, 25, 50, 100, 150, and 200 mg/day) were administered biweekly. Additional increases for patients were allowed to 400 mg/day in biweekly 50-mg/day increments as well as adjustments to concomitant ASMs.
Clinical Takeaways
- Early adjustments to adjunctive antiseizure medications positively impacts cenobamate retention, emphasizing the significance of proactive dosage management in epilepsy.
- Pharmacokinetic interactions with substrates such as clobazam highlight the need for informed and timely adjustments, contributing to improved tolerability.
- The post-hoc analysis provides valuable insights into optimizing cenobamate treatment, influencing both dosage strategies and overall tolerability in epilepsy management.
Among 1340 patients included, CYP2C19 substrates clobazam (Onfi; Lundbeck), phenytoin, and phenobarbital had pharmacokinectic interactions with cenobamate and led to increased plasma exposure and early dose reductions. In week 52 of the study, the total clobazam dose was reduced by a mean of 30.9% and the total daily dose of lacosamide (Vimpat; UCB) decreased by 21.7% by the fourteenth visit. As the investigators gained more experience, it was noted that these dose reductions were made earlier and more proactively, which reflected current consensus recommendations.2
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In the post hoc analysis, researchers examined dose reductions of ASMs which included lacosamide, levetiracetam (Keppra; UCB), lamotrigine (Lamitcal; GSK), clobazam, phenytoin, phenobarbital, and carbamazepine. Findings showed that the potential PK interactions between cenobamate, carbamazepine, and lamotrigine might cause a reduction in plasma exposure to those ASMs. All told, a majority of concomitant carbamazepine and lamotrigine dosages were reduced or unchanged for patients during the study.
The authors also noted that these dose reductions may have led to better tolerability of cenobamate and permitted for successful up-titration of the therapy. Similarly, although the cenobamate did not cause changes to plasma exposure in lacosamide, the PD interactions likely resulted in dose reductions to enhance tolerability as the cenobamate dose increased. Additionally, maintenance-phase dose reductions of levetiracetam, which had no known PK/PD interactions with cenobamate, were likely intended to decrease overall medication burden.
In a similar post-hoc analysis of a subset (n = 240) of patients from Study C021, findings reported on how patients adjusted baseline ASMs while on cenobamate.2 The most commonly reported baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide (Zonegran; Eisai), and clobazam. For these ASMs, mean dose reductions and percentage change in dose from baseline to last dose were greater in patients continuing cenobamate vs those who discontinued.
The greater retention rate for these ASMs—ranging from 71.9% to 78.9% for patients who continued cenobamate and from 21.1% to 28.1% for those who discontinued the study drug—were observed for those who had larger concomitant ASM dose reductions. The percent dose change ranged from –65.8% to –23.4% for those continuing the study drug compared with –7.8% to –25.0% for those who discontinued. The findings suggest that “the cenobamate efficacy was not impaired by decreasing the dose of concomitant ASMs, and that cenobamate tolerability may have improved with greater concomitant ASM dose reductions,” according to investigators.2
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REFERENCES
1. Ferrari L, Kamin M, Rosenfeld W. Dose Reduction Timing for Concomitant Antiseizure Medications: Post-hoc Analysis of a Phase 3, Open-Label Study of Cenobamate for Treatment of Uncontrolled Focal Seizures. Presented at: AES 2023; December 1-5; Orlando, FL. Abstract 1.278
2. Rosenfeld WE, Abou-Khalil B, Aboumatar S, et al. Post hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications. Epilepsia. 2021;62(12):3016-3028. doi:10.1111/epi.17092
3. Smith MC, Klein P, Krauss GL, et al. Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations. Neurol Ther. 2022;11(4):1705-1720. doi:10.1007/s40120-022-00400-5
