Abstracts

Rationale: Cenobamate is a novel antiepileptic drug (AED) in development for treatment of uncontrolled focal (partial-onset) seizures. Multiple studies were conducted to evaluate effects of age, renal impairment (RI), hepatic impairment (HI), food, and coadministration of other AEDs and various cytochrome P450 (CYP) probes on the pharmacokinetics (PK) and safety of cenobamate. Methods: Healthy young (18-45 years old; n=12) and elderly (>=65 years old; n=12) subjects were included in the age effect study. Mild RI (n=8), moderate RI (n=6), and normal renal function (n=8) subjects comprised the RI study and mild HI, moderate HI, and normal hepatic function (n=8 each) subjects were included in the HI study. All other studies included healthy adults (n=18 and n=16, cenobamate 200 mg and 300 mg, food effect study; n=80 drug-drug interaction (DDI) study; n=24 CYP probe study). Geometric mean ratios of Cmax, AUC0-t, AUCinf, and 90% CIs were calculated for test vs reference groups, with absence of an effect concluded if 90% CIs lay within reference range (0.80-1.25). Results: In elderly vs. young subjects, no significant difference in Cmax was observed, while AUC values were slightly higher but not clinically meaningful. Cenobamate Cmax was within reference range for both mild and moderate RI vs normal subjects; AUC values were ~1.5-fold higher in mild and moderate RI vs normal subjects. Cenobamate Cmax was ~20% higher in mild HI vs normal subjects (deemed not clinically meaningful), and no significant difference between moderate HI and normal subjects was seen. An ~2-fold increase in AUC was observed in mild and moderate HI vs normal subjects. Administration of cenobamate 200 mg with food led to ~1 h delay in median tmax and AUC values with either dose were comparable in fed vs fasted conditions. DDI study results indicated combination treatment with cenobamate and phenobarbital, carbamazepine, or divalproex led to limited or no effect on cenobamate systemic exposure. Phenytoin significantly decreased cenobamate Cmax and AUC0-t. Coadministration of cenobamate resulted in increased Cmax and AUC0-t of phenobarbital and phenytoin and decreased exposure for carbamazepine. In the CYP probe study, cenobamate 200 mg/day led to an induction of CYP2B6 activity (bupropion probe), a moderate induction of CYP3A (midazolam probe), and inhibited CYP2C19 (omeprazole probe) with high variability. A smaller induction of CYP3A (midazolam probe) was seen with cenobamate 100 mg/day, indicating a dose-dependent effect. No significant effects on CYP2C9 (warfarin probe) were observed. Results demonstrated that cenobamate was generally safe and well-tolerated in all studies. Conclusions: The results of these studies provide a strong knowledge on the disposition of cenobamate in special populations and in combination with other drugs, which will be used to provide appropriate dosing recommendations. Funding: SK Life Science, Inc.