Epilepsia · 2026
Pharmacokinetic variability and complex two-way interactions with cenobamate in patients with refractory epilepsy.
СтатьяНаблюдательное исследованиеНазвание и аннотация: Перевод в очереди
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Johannessen Landmark Cecilie, Belkilani Heba, Awad Lilyana, Burns Margrete Larsen, Gottås André, Svendsen Torleiv, Sætre Erik
Аннотация
OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
SIGNIFICANCE: 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.
METHODS: 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.
RESULTS: 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.
SIGNIFICANCE: 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.