Integrating Therapeutic Drug Monitoring and Metabolomics to Explore Interindividual Variability in Lamotrigine Response in Epilepsy

Objective: Lamotrigine (LTG) is a first-line antiseizure medication, yet substantial interindividual variability in therapeutic response remains a major clinical challenge. This study integrated therapeutic drug monitoring (TDM) and metabolomics to explore pharmacokinetic and metabolic factors associated with LTG efficacy in patients with epilepsy. Methods: A total of 141 epilepsy patients receiving LTG therapy were retrospectively enrolled and classified as responders or non‑responders by 6-month seizure frequency reduction. LTG plasma concentrations were measured using HPLC–DAD. Untargeted UPLC–MS/MS metabolomics and multivariate analysis were performed on serum from 10 responders and 10 non-responders with LTG > 5.15 mg/L, with differential amino acids quantified. Differential metabolites were further quantified, with a focus on amino acids. Results: Mean LTG plasma concentration was significantly higher in responders (7.55 ± 4.57 mg/L) than non‑responders (4.53 ± 2.94 mg/L; P = 0.001). Receiver operating characteristic (ROC) curve analysis suggested 5.15 mg/L as the optimal cut‑off for discriminating responders from non‑responders, within the conventional ILAE reference range (2.5– 15 mg/L). Concomitant use of valproic acid (VPA) increased LTG exposure, was more prevalent among responders, and enabled seizure control at lower LTG doses. Metabolomic analysis in the high‑concentration subgroup revealed a distinct amino acid profile in responders, characterized by higher proline and lower lysine and cystine (P < 0.05). These changes suggest reduced oxidative stress and improved neuronal stability in responders. Conclusion: Higher LTG plasma concentrations were associated with better seizure control, and VPA co‑administration enhances LTG exposure and efficacy. The distinct amino acid profile in high-concentration responders suggests amino acid metabolism and redox balance may modulate LTG efficacy. Infographic on epilepsy treatment: cohort, TDM and metabolomics for therapy optimization.On the left, it mentions a cohort of 141 patients with epilepsy receiving LTG, divided into responders (greater than or equal to 50 percent seizure reduction in 6 months) and non-responders. The middle section, labeled TDM, displays a bar graph with a cut-off at 5.15 milligrams per liter, indicating responders with 7.55 milligrams per liter and non-responders with 4.53 milligrams per liter. It notes that valproic acid co-medication increases LTG exposure. The right section, labeled Metabolomics, shows a diagram with proline increasing, lysine and cystine decreasing, indicating a distinct metabolic signature associated with a favorable response. A note at the bottom states that higher LTT concentration leads to better seizure control and TDM plus metabolomics support individualized therapy optimization. Keywords: lamotrigine, epilepsy, therapeutic drug monitoring, metabolomics, amino acid