Pharmacokinetic variability and complex two-way interactions with cenobamate in patients with refractory epilepsy

Cenobamate (CNB) is a new antiseizure medication (ASM) for add-on therapy in adults with refractory epilepsy. The purpose of this study was to investigate the pharmacokinetic variability of CNB and extent of interactions with other ASMs.

In this observational therapeutic drug monitoring (TDM) study we included all patients with serum concentrations of CNB and concomitantly used ASMs (2022-2025) from the Section for Clinical Pharmacology, National Center for Epilepsy, Oslo University Hospital.

Data from 258 patients included 672 serum CNB concentration measurements (1-7 per patient; 56% women; median age = 36 years, range = 11-77). Mean daily dose and serum concentration at the most recent measurement were 164 mg/day (range = 12.5-400, SD = 88.6) and 53.7 μmol L^-1 (range 5-186, SD = 34.8). Intraindividual variation in CNB concentration/dose (C/D) ratios ranged from 6% to 33% (coefficient of variation = 18%); interpatient variability was 34-fold. Comedication was a contributing but variable factor. Mean CNB C/D ratios were affected by strong enzyme inducers (-9%) and inhibitors (+14%) as compared to neutral ASMs (p < .05). Twenty-four concomitant ASMs were used (1-6 per patient, mean = 1.91, SD = .94); clobazam, lamotrigine, and valproate were the most common. After initiating CNB, significant but variable increases in mean C/D ratios of desmethylclobazam (+233%, and +344% for the Cd-clb/Cclb€ ratio, n = 57) and phenobarbital (+36%, n = 15) were observed, as were decreases for lamotrigine (-28%, n = 57) and carbamazepine (-26%, n = 7) (p < .05). For most other ASMs, there were unpredictable changes in individual C/D ratios.

We demonstrate complex and unpredictable two-way interactions in polytherapy with CNB and pronounced pharmacokinetic variability among patients with refractory epilepsy, elucidating the usefulness of TDM.