Abstracts

Rationale: The approval of cenobamate for the treatment of focal seizures in adults was based on adjunctive therapy studies. For labeling development purposes, the U.S. Food and Drug Administration (FDA) determined it is acceptable to extrapolate the efficacy and safety of drugs approved as adjunctive therapy for their use as monotherapy. To support monotherapy use, the drug dosages used as monotherapy should result in exposures that are similar to those demonstrated to be safe and effective when the drug is used as adjunctive therapy for the treatment of focal seizures.

Methods: A population pharmacokinetic (PK) model-based analysis of pooled data from clinical studies conducted in healthy subjects, special populations, and patients with focal seizures was used to evaluate expected exposure to cenobamate when used as monotherapy compared to adjunctive therapy. Repeated daily maintenance dosing of cenobamate at 100, 200, and 400 mg was used to simulate plasma exposure, expressed as area under the plasma concentration vs. time curve (AUC). The following antiseizure medications (ASMs) were tested as covariates for statistically significant effects on the apparent clearance (CL/F) of cenobamate based on their use in the clinical studies of patients with focal seizures: carbamazepine, clobazam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate. ASMs with a statistically significant effect on the clearance of cenobamate were used as the adjunctive therapy in the comparison with monotherapy. Treatment equivalence was determined if the derived 90% confidence interval (CI) of the ratio, defined as the log of AUC under cenobamate monotherapy divided by the log of the simulated AUC when given as adjunctive therapy, fell within 0.8 and 1.25 (i.e., no effect).

Results: Lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate did not show any statistically significant effects on apparent clearance of cenobamate in the population PK model. Clobazam and carbamazepine did show statistically significant effects on apparent clearance; however, the derived 90% CIs of the monotherapy/adjunctive therapy ratios fell within the 0.8 to 1.25 limit. Therefore, plasma cenobamate exposures with adjunctive therapy were comparable to monotherapy.

Conclusions: Based on these findings, cenobamate monotherapy should result in plasma exposures comparable to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures.

Funding: Funded by SK Life Science, Inc.