Authors :
Presenting Author: Isabel Toghramadjian, – Northwestern University
Anthony Jimenez, BS – Yale University School of Medicine
Chinenye Okafor, MBBS, MPH – Medical University of South Carolina
Aurélie Hanin, PharmD, PhD – Yale University School of Medicine
Hamada Altalib, DO, MPH – Yale University School of Medicine
Aline Herlopian, MD – Yale University
Rationale:
Cenobamate (CNB) has significant drug-drug interactions (DDIs), causing mild to severe/life-threatening adverse effects (AEs), prompting CNB discontinuation. We explore these DDIs by analyzing CNB serum levels and concomitant anti-seizure medications (ASMs). We investigate the side effect profile by studying CNB serum levels. Our goal is to provide sufficient evidence, guiding dosing strategies to improve tolerability and seizure control.
Methods:
413 patients were taking CNB between 2020 and 2024 in a single level 4 epilepsy center. Fifty-six patients had at least one concomitant anti-seizure medication (ASM) with a minimum of four serum levels two before and two after CNB alongside two CNB levels. Concentration-to-Dose Ratio (CDR) was calculated, accounting for the impact of dosage variations on serum levels. The median percent changes in patients’ CDR before and after CNB initiation were then compared. A descriptive analysis was performed using available serum concentrations of CNB and concomitant ASM, and qualitative measures of patient-reported AEs.
Results:
An analysis of all available CNB levels (398 levels from 151 patients) revealed that the interquartile ranges (IQRs) of CNB concentrations (ug/ml) varied by dose, reflecting a dose-dependent increase in serum levels (figure 1). The median level per dose followed a linear distribution with slope 0.0912 µg/mL/mg, with R2=0.998.
As for the changes in the ASM levels when co-administered with CNB, Lamotrigine, Clobazam, Carbamazepine, and Topiramate showed negative median percent changes in CDR when taken with CNB as opposed to Levetiracetam, Phenobarbital, Lacosamide, Valproic Acid, and Zonisamide.
As for AEs, the median CNB serum level at onset is 11 ug/ml (Median absolute deviation: MAD 4.9 ug/ml). AEs resolved in 52 (48.15%) patients, persisted but were tolerable in 26 (24.07%), improved in 23 (21.30%), and worsened in 7 (6.48%). Among the resolved patients, only 21 patients continued CNB, while the remaining discontinued CNB, leading to AEs resolution. The median serum level at the time of AEs resolution was 14 ug/ml (MAD 5.3 ug/ml) (p-value: 0.118).
Conclusions:
We demonstrate important critically relevant information regarding CNB in the day-to-day epilepsy practice: 1) dose-dependent increase in CNB serum levels, 2) consistent trends in the change of ASM serum levels when administered with CNB, and 3) serum levels are not reliable biomarkers to reflect SEs profiles.
Funding: NA