Objective:

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.

Background:

Design/Methods:

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 clinical studies of patients with focal seizures: carbamazepine, clobazam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate. ASMs with a statistically significant effect on the CL/F 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 of the AUC log under cenobamate monotherapy, divided by the simulated AUC log when given as adjunctive therapy, fell within 0.8-1.25 (ie, no effect).

Results:

Lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate did not show any statistically significant effects on CL/F of cenobamate in the population PK model. Clobazam and carbamazepine showed statistically significant effects on CL/F; however, the derived 90% CIs of the monotherapy/adjunctive therapy ratios fell within the 0.8-1.25 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.