Authors :
Presenting Author: Louis Ferrari, RPh, MBA – SK Life Science, Inc.
Marc Kamin, MD – SK Life Science, Inc.; William Rosenfeld, MD – Comprehensive Epilepsy Care Center for Children and Adults
Rationale:
Cenobamate is an antiseizure medication (ASM) approved in the United States (XCOPRI®) and Europe (ONTOZRY®) for the treatment of focal seizures in adult patients. Pharmacokinetic (PK) and pharmacodynamic (PD) interactions between cenobamate and other ASMs may cause efficacy/tolerability issues. A post-hoc analysis of a subset (n=240) of patients from a phase 3 safety and efficacy study of adjunctive cenobamate (Study C021) indicated that reducing doses of concomitant ASMs led to better cenobamate retention (Rosenfeld 2021 Epilepsia. 62(12):3016-28). Investigators learned about potential interactions from the open-label nature of the study. Early strategic dose adjustments of concomitant ASMs during the study suggested that ASM lowering may occur even earlier in clinical practice. The current post-hoc analysis examined how investigators adjusted the dose of concomitant ASMs in the full C021 patient population (n=1340).
Methods:
Study C021 enrolled patients with uncontrolled focal seizures taking one to three ASMs. 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. Adjustments to concomitant ASMs were allowed. Dose reductions of the following concomitant ASMs were examined: clobazam, phenytoin, phenobarbital, carbamazepine, lamotrigine, lacosamide, and levetiracetam.
Results: For CYP2C19 substrates clobazam, phenytoin, and phenobarbital, PK interactions resulted in increased plasma exposure and early dose reductions (Figure 1). By Visit 14 (Week 52 of study), mean decrease in total clobazam dose was 30.9%; as investigators gained experience, these dose reductions were made earlier and more proactively, as reflected by current consensus recommendations (Smith 2022 Neurol Ther. 11(4):1705-20). Potential PK interactions between cenobamate, carbamazepine, and lamotrigine may cause decreased plasma exposure to those ASMs. During the study, most concomitant carbamazepine and lamotrigine dosages were lowered or unchanged. These dose decreases may have led to better tolerability of cenobamate and allowed for successful up titration of cenobamate (Figure 2). Similarly, although cenobamate does not cause changes to plasma exposure in lacosamide, PD interactions likely resulted in dose reductions to improve tolerability as the cenobamate dose increased. By Visit 14, the total daily dose of lacosamide was decreased by 21.7%. Maintenance-phase dose decreases of levetiracetam, which has no known PK/PD interactions with cenobamate, were likely intended to reduce overall drug burden (Figure 2).
Conclusions:
These results support the concept that dosages of adjunctive ASMs (e.g., clobazam, phenytoin, phenobarbital, lacosamide) should be adjusted early in the treatment with cenobamate. In a subset of these patients, results informed recommendations for even earlier and larger reductions in these agents in clinical practice (Smith 2022, Rosenfeld 2021). Funding:
Funded by SK Life Science, Inc.