Pharmacokinetics of Cenobamate (YKP3089): Results From Single and Multiple Oral Rising-Dose Studies in Healthy Subjects (P5.280)

Objective: To characterize the pharmacokinetics (PK) of cenobamate after single- and multiple-dose administration. Background: Cenobamate (YKP3089) is an investigational antiepileptic drug currently in development for the treatment of adults with partial-onset seizures. Design/Methods: Three randomized, placebo-controlled, double-blind studies were conducted in 180 healthy subjects receiving single oral doses (from 5 to 750 mg) or multiple oral doses (from 50 to 300 mg/day) of cenobamate using capsule formulation. Safety assessments included adverse events (AEs) and laboratory evaluations. Results: Maximum plasma concentration of cenobamate was observed between 0.75 and 6 h after oral administration. Area under the plasma concentration–time curve of cenobamate increased in a more than dose-proportional manner. Over the tested dose range, cenobamate exhibited moderate volume of distribution (~37–55 L), low oral clearance decreased from ~1.4 to 0.40 L/h with dose increase, and long terminal half-life (t 1/2 ) increased from ~30 to ~76 h with dose increase. Within the 200–300 mg/day therapeutic range, t 1/2 ranged between 55 and 60 h. PK parameters observed after multiple doses of cenobamate were consistent with the single-dose data. Steady state was attained after ~2 weeks and the accumulation index was ~5 over the 50–300 mg/day dose range. Most AEs were deemed mild in severity, and no serious AEs were reported. Conclusions: The disposition of cenobamate exhibits some degree of non-proportionality, especially after single oral dose administration. The PK characteristics of cenobamate are consistent with once-daily dosing. Single doses (up to 750 mg) and multiple doses (up to 300 mg/day) of cenobamate are generally well tolerated. Disclosure: Dr. Vernillet has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SK Life Science. Dr. Kamin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SK Life Science.