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

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.

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.

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.

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.