Monitorowanie stężenia leków oraz analiza metabolitów w badaniu różnic w odpowiedzi organizmu na lamotryginę u pacjentów z epilepsją
Integrating Therapeutic Drug Monitoring and Metabolomics to Explore Interindividual Variability in Lamotrigine Response in Epilepsy
W skrócie
Badanie wykazało, że pacjenci, u których lamotrogina skutecznie kontrolowała napady padaczki, mieli wyższe stężenie tego leku we krwi niż ci, u których leczenie było mniej skuteczne. Okazało się również, że połączenie lamotroginy z innym lekiem (kwasem walproinowym) poprawia efekt terapeutyczny. Analiza chemiczna krwi wykazała, że u pacjentów, u których leczenie się powiodło, zaobserwowano inne proporcje aminokwasów, co może wskazywać na zmniejszone stres oksydacyjny i lepszą stabilność komórek mózgowych.
Oryginalny abstract (angielski)
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.