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. Alcohol (ethanol, EtOH) can have pharmacodynamic (PD) and pharmacokinetic (PK) interactions with psychoactive drugs; this study assessed PD and PK interactions when EtOH and CNB are co-administered. Methods: In this phase 1, 4-way crossover, double-blind, single-dose study, healthy males/females were randomized to a sequence of 4 treatments (CNB 200 mg + EtOH placebo; CNB 200 mg + EtOH; CNB placebo + EtOH; CNB placebo + EtOH placebo) with 21-day washouts between treatments. EtOH (40%) was dosed at 0.7 g/kg (males) and 0.57 g/kg (females). Subjects were confined for 60 hours during each study period. Primary PD endpoint was an objective central nervous system (CNS) evaluation using the Digit Vigilance (DV) test. Secondary PD endpoints included subjective CNS assessment using the Bond & Lader Visual Analog Scale (VAS). Drug-alcohol interactions were evaluated using ANOVA applied to a 2x2 factorial interaction model on changes from baseline. Orthogonal contrasts were computed using a t-test (alpha max, AUC_0-tlast, and AUC_0-inf. No effect on plasma exposure was considered if 90% CIs for treatment ratios were between 0.80-1.25. Safety was assessed through adverse events (AE), physical exams, and clinical laboratory tests. Results: Thirty-two subjects were randomized (male, n=19; female, n=13) and 27 completed the study. EtOH had expected negative results on the DV test, with significant impairments observed in attention, increased mean reaction time (at 1h, 3h, 6h), increased number of false alarms, and decreased number of correctly identified targets (both at 3h) (all p<0.05). Conversely, CNB significantly decreased number of false alarms (at 3h, p<0.05) and had no other effect on DV parameters. No significant interaction of DV parameters were seen with CNB and EtOH co-administration. EtOH significantly decreased all 3 VAS scores over 6 hours; CNB + placebo and CNB + EtOH had no significant effect on VAS parameters. Statistical analyses for C_max, AUC_0-inf, and AUC_0-tlast indicated EtOH had no effect on CNB exposure and CNB had no effect on PK of EtOH (90% CIs for both fell within reference ranges). No significant safety signals and no clinically relevant abnormalities in laboratory values, vital signs, ECGs, or exams were observed during the study. Conclusions: No PD interactions between CNB and ethanol were observed on the DV test and CNB administration did not result in clinically relevant impairments of CNS measures. CNB did not potentiate any sedative effects of EtOH, and no PD interaction was observed overall. Co-administration of CNB with EtOH had no effect on PK of either EtOH or CNB. CNB and EtOH administered together and separately were safe and well-tolerated. Funding: SK Life Science, Inc.