Abstracts

Rationale: Cenobamate (YKP3089, CNB) is a novel AED in development for treatment of partial-onset seizures. CNB modulates GABA-mediated currents, and modulates several properties of voltage-gated Na+ ion channels, with preferential inhibition of the persistent Na+ current. CNB undergoes extensive metabolism in humans (about 85% of the dose) and is primarily eliminated in urine (88% of the dose); thus, the PK of CNB was investigated in 2 separate studies in hepatically impaired subjects and in elderly subjects. Methods: Two phase 1, open-label, single-dose, 16-day studies were conducted in male and female subjects. The hepatic impairment (HI) study was conducted in normal subjects and in subjects with mild or moderate HI per Child-Pugh classification. The elderly study assessed effect of age on CNB PK in young (18-45 years old) and elderly (=65 years old) subjects. A single 200-mg dose of CNB was administered orally to each subject. Primary endpoints for the hepatic study were the effects of HI on the plasma PK exposure parameters (C_max, AUC_last, and AUC_0-inf). For the elderly study, the primary objective was to assess the effect of age on the PK of CNB. The secondary endpoint for both studies was safety following single-dose administration of cenobamate. An analysis of variance model was used to compare PK parameters between normal and HI subject groups, or young and old subject groups. Geometric least-squares mean ratios between the HI group vs normal subjects and elderly group vs young subjects were calculated, along with 90% CIs. If 90% CIs of the geometric mean ratios were between 0.80-1.25, no effect of HI or age of the cenobamate PK was concluded. Results: PK populations: 24 subjects (n=8 per group) completed the hepatic study and were evaluable; 24 subjects (young, n=12; elderly, n=12) completed the elderly study and were evaluable. Subjects with mild or moderate HI had ~2-fold greater AUC_last and AUC_0-inf vs normal subjects, whereas a limited effect on C_max was seen in both mild and moderate HI subjects. Elderly subjects showed a slightly higher plasma exposure compared to younger subjects for both AUC parameters, leading to 90% CIs that were slightly over the boundaries (AUC_last, 0.86-1.34; AUC_0-inf, 0.85-1.33). Cenobamate C_max was comparable between the 2 age groups. CNB was safe and well tolerated, with 1 serious AE across both trials (elderly study: hypertension, not treatment-related). No deaths and no clinically relevant changes in lab results were observed across either study. Conclusions: The results of these two studies indicate that subjects with mild or moderate HI would likely require lower therapeutic doses of CNB compared to those with normal hepatic function. A dose adjustment of cenobamate in elderly subjects would likely not be necessary. CNB was safe and well tolerated in HI and elderly subjects. Funding: SK Life Science, Inc.