Abstract Details

Title Pharmacokinetic Interaction Between Cenobamate and Lamotrigine: Real-world Evidence from a Single-center Cohort

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P3 - Poster Session 3 (5:00 PM-6:00 PM)

Poster/Presentation
Number 10-002

Objective

To characterize pharmacokinetic changes in lamotrigine (LMT) levels and associated clinical outcomes following cenobamate (CNB) initiation.

Background

LMT is commonly co-prescribed with CNB in patients with refractory focal epilepsy. LMT is metabolized primarily via glucuronidation and to a lesser extent by CYP3A4. CNB acts as both an inducer and inhibitor of various cytochrome P450 enzymes, contributing to numerous pharmacokinetic interactions, particularly in polytherapy. Induction of CYP3A4 by CNB may enhance lamotrigine metabolism; however, real-world pharmacokinetic data on this interaction remain limited.

Design/Methods We retrospectively analyzed adults co-treated with LMT and CNB. Paired pre- and post-CNB LMT serum concentrations and doses were compared using Wilcoxon signed-rank tests and geometric mean ratio (GMR) analyses. Clinical outcomes were assessed for ≥50% and ≥75% seizure reduction and ≥6-month seizure freedom.

Results Fifty-seven patients (44% female; median age 41 [33–56]) were included. Median baseline LMT concentration was 11.9 µg/mL (8.2–14.6) at a median dose of 400 mg/day, decreasing to 8.6 µg/mL (5.1–11.3) post-CNB, with unchanged dosing. The geometric mean ratio (post/pre) was 0.67 (95% CI 0.59–0.76) for serum concentration and 0.69 (95% CI 0.60–0.78) for the concentration-to-dose ratio, indicating a 30–33% reduction in lamotrigine exposure independent of dose adjustment. The median absolute change in serum concentration was −2.8 µg/mL (p < 0.001), corresponding to a 28.1% median percent reduction. Minimal shifts occurred across therapeutic ranges: 8.8% transitioned from therapeutic to subtherapeutic levels (<3 µg/mL), and 7% from supratherapeutic (>15 µg/mL) to within range, with no reported toxicity. Clinically, 36/55 (65.5%) achieved ≥50% , 22/55 (40%) achieved ≥75% seizure reduction, and 14/55 (25.5%) achieved ≥6-month seizure freedom.

Conclusions Cenobamate induces CYP3A4-mediated metabolism of lamotrigine, leading to an approximate 30% reduction in serum levels. Awareness of this interaction is important during CNB initiation, as reduced LMT exposure may require higher doses of LMT to maintain appropriate serum concentrations and avoid breakthrough seizures.

Authors/Disclosures
Venkata Sai Manikant Sanikommu PRESENTER	Venkata Sai Manikant Sanikommu has received personal compensation for serving as an employee of University Of Miami.
Yensea M. Costas Encarnacion, MD	Dr. Costas Encarnacion has nothing to disclose.
Tiffany A. Eatz, MD (University of Miami Miller School of Medicine)	Dr. Eatz has nothing to disclose.
CARLOS MAURICIO M. MILLAN, MD	Dr. Millan has nothing to disclose.
Andres M. Kanner, MD, FAAN (University of Miami, Miller School of Medicine, Department of Neurology)	Dr. Kanner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Kanner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Xenon. Dr. Kanner has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsy Foundation of America. Dr. Kanner has received personal compensation in the range of $500-$4,999 for serving as a Lecture at International meeting with Eisai.

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