Objective:

This population pharmacokinetic (PPK) analysis compared the pharmacokinetics (PK) properties of cenobamate in adult (18 to <65 years of age) and elderly subjects (≥65 years of age).

Background:

Cenobamate is a novel small molecule approved as an oral tablet formulation in several countries for the treatment of focal (partial-onset) seizures with a maintenance dose of 200 mg (range, 100-400 mg).

Design/Methods:

A PPK model was developed based on available data from phase 1 and phase 3 studies. The final best-fit model was qualified by standard numerical and graphical goodness-of-fit (GOF) checks, including visual predictive check (VPC). Nonlinear mixed-effects methods were implemented in NONMEM (version 7.4.3). In a second step, age, bodyweight, and creatinine clearance (CrCL) vectors were resampled from 10,000 virtual subjects. The exposures (AUC values) were simulated for these virtual subjects.

Results:

Available data from 988 participants (n=933 adults 18 to <65 years; n=55 elderly adults ≥65 years) from phase 1 and phase 3 clinical trials were included in the PPK model. The GOF checks indicated that the final model fitted well to the observed data. There was good agreement in the time course and central tendency between distributions of observed and simulated data, with no obvious bias. The estimated interindividual variability adequately described the observed variability in plasma cenobamate concentrations. Cenobamate’s PK properties were adequately described by a two-compartment model with first-order absorption and first-order elimination. The estimated CL/F, V1/F, and V2/F were 0.282 L/hr, 38.6 L, and 6.72 L, respectively. While simulations indicated that mean exposure was approximately 21% higher in elderly vs adult subjects, overall exposures in adult subjects and elderly subjects were considerably overlapping and comparable across a range of clinically approved maintenance doses in adults (100-400 mg).

Conclusions:

Cenobamate exposures were similar in adult (18 to <65 years of age) and elderly (≥65 years of age) subjects.