066: Population Pharmacokinetic Analysis of Cenobamate

Statement of Purpose, Innovation or Hypothesis: SK Life Science Inc has developed cenobamate, a small molecule drug, which is now approved and marketed for focal seizures (partial-onset seizures) in several countries under the brand names of Xcopri® or Ontozry®. A population pharmacokinetic (PK) analysis was performed to describe cenobamate plasma concentration-time profiles and characterize variability in the PK following oral administration. Covariate analyses focused on age, body weight (WT), gender and concomitant anti-seizure medications that may potentially influence the disposition of cenobamate. The purpose of this population PK analysis was to describe cenobamate PK and identify clinically meaningful covariates on its drug disposition.

Description of Methods & Materials: Cenobamate data were pooled from eight Phase 1, two Phase 2 and one Phase 3 studies. The Phase 1 studies included healthy, elderly, renally impaired and hepatically impaired subjects, whereas the Phase 2 and 3 studies included patients with focal seizures. The analysis dataset included 8,700 observations from 960 subjects at the dose range of 5 to 750 mg (single dose) and 50 to 600 mg/day (multiple dose). Most of the data were derived from multiple dosing at 100 mg/day (14.2% of subjects), 200 mg/day (67.5%) and 400 mg/day (9.3%). Non-linear mixed effects methods were implemented in NONMEM to describe plasma PK of cenobamate, as well as the data variability between subjects, or inter-individual variability (IIV), as a function of time, dose, disease status and other subject characteristics. Initially, a structural model was developed followed by random effect models. Subsequently, covariates were screened using a stepwise approach. The final best-fit model was qualified by standard numerical and graphical goodness of fit (GOF) checks, including visual predictive check (VPC).

Data & Results: Cenobamate plasma PK was well-described by a two-compartment model with a first-order, absorption lag and dose-dependent elimination parameter that accounted for non-linearity in drug exposures below 200 mg, or the maintenance therapeutic daily dose. The estimated CL/F was 0.53 L/h, V1/F of 42.4 Liters and V2/F of 7.27 Liters. Race/ethnicity was associated with changes in both CL/F and V1/F, with African American subjects having a median 17.2%-higher AUC than non-African American subjects. Hispanic ethnicity, carbamazepine and clobazam intake were associated with a change in cenobamate CL/F of 13% decrease, 15% increase and 19% decrease, respectively. In addition, a linear effect was seen on the CL/F of cenobamate with bilirubin concentrations and body weight (that is collinear to body surface area). No statistically significant effects on CL/F were seen with the concomitant use of lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate or valproate with cenobamate. No significant PK differences were observed between healthy subjects and patients with focal seizures. While race/ethnicity was identified as a statistically significant covariate, it may not be clinically meaningful to modify the cenobamate dosing regimen for these populations based on past clinical studies.

Interpretation, Conclusion or Significance: The model described cenobamate PK well and can be used for predicting plasma cenobamate exposure with repeated oral dosing in subjects with focal seizures in subsequent exposure-response analyses.

Disclosures: This study was funded by SK Life Science Inc. FJ: Employee, qPharmetra LLC. qPharmetra was contracted by SK Life Science Inc to perform this study. JKL, VV: Employees, SK Life Science Inc.

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Additional Information/Authors: This study was funded by SK Life Science, Inc.