(634) Cenobamate Trough Plasma Concentrations in Patients with Uncontrolled Focal Seizures Achieving 50% and 100% Seizure Reduction in Two Randomized Clinical Studies

Rationale: Cenobamate (CNB) is an antiseizure medication (ASM) recently approved in the U.S. for treatment of focal (partial-onset) seizures in adults. Two adequate and well controlled studies (YKP3089C013 [C013] and YKP3089C017 [C017]), each with a titration and maintenance phase, demonstrated that patients randomized to adjunctive treatment with CNB 100, 200, and 400 mg/day had significantly decreased focal seizure frequency compared to placebo. As with most ASMs, epilepsy patients should be titrated to a CNB dose that provides the best efficacy with acceptable tolerability. In some instances, plasma concentrations may be used to aid physicians in evaluating compliance, breakthrough seizures, side effects, etc. A suggested reference concentration range for CNB was determined by analyzing steady state trough plasma concentrations during the maintenance phase of both studies in patients who achieved 50% seizure reduction (50% SR) and seizure freedom (SF; 100% seizure reduction).

Methods: In study C013, after a six-week titration to a target dose of 200 mg, patients were maintained on their attained dose during a six-week maintenance phase. In study C017, after a six-week titration to target doses of 100, 200, or 400 mg/day patients were maintained on their attained dose during a 12-week maintenance phase. In both studies patients were taking one to three additional ASMs. Trough CNB plasma concentrations were obtained periodically during the maintenance phase of each study. Average CNB concentrations were associated with each patient who achieved 50% SR and SF at doses of 100 (n=42, n=4, respectively), 200 (n=95, n=32, respectively) or 400 mg/day (n=50, n=18, respectively) during the maintenance phase. Box (including 90% of patients in each category) and whisker (entire range) plots comparing the three CNB dose groups were developed. A C_trough range that covered at least 95% of the total population for 50% SR and SF was determined. A toxic range was not established.

Results: The range of concentrations (µg/mL) during the maintenance phase for 90% of patients with 50% SR taking 100 mg/day was 4.6-9.3, taking 200 mg/day was 11.3-18.7, and taking 400 mg/day was 20.8-35.2 (Figure 1). The range of concentrations (µg/mL) during the maintenance phase for 90% of patients with SF taking 100 mg/day was 5.1-9.7, taking 200 mg/day was 10.8-19.8, and taking 400 mg/day was 21.9-35.8 (Figure 2). Overall, CNB trough concentrations for 95% of patients with 50% SR or SF lay between 5 µg/mL and 35 µg/mL.

Conclusions: Based on results from two adequate and well controlled studies of adjunctive CNB in patients with focal seizures taking one to three other ASMs, a suggested trough plasma concentration reference range (not a target therapeutic range) of 5-35 µg/mL covered 95% of patients who achieved 50% seizure reduction or 100% seizure reduction.

Funding: Please list any funding that was received in support of this abstract.: SK Life Science, Inc.
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