Pharmacokinetic Interaction Between Cenobamate and Lamotrigine: Real-world Evidence from a Single-center Cohort
Yensea Costas Encarnacion1, Sai Sanikommu2, Tiffany A. Eatz1, CARLOS MAURICIO MILLAN1, Andres Kanner3
1Department of Neurology, 2Department of Neurosurgery, University of Miami, Miller School of Medicine, 3Department of Neurology, University of Miami, Miller School of Medicine, Department of Neurology
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.
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