Purpose: Therapeutic drug monitoring (TDM) is increasingly recommended in antiepileptic drug (AED) therapy, yet a complex relationship exists between the unbound-drug serum concentration (Cu.serum) as a monitoring biomarker and clinical efficacy. The study was designed to investigate the validity of the intracellular unbound-drug concentration in Peripheral Blood Mononuclear Cells (Cu.PBMC) as a feasible TDM tool in relation to levetiracetam (LEV).
Methods: Patients from epilepsy out-patient centre were included in a 4-month descriptive prospective study. Trough serum and PBMC LEV concentrations were monthly determined using HPLC and correlated with clinical features, demographic data, and P-glycoprotein (P-gp) expression.
Results: Seventy-patients completed the study with a LEV dose range of 500-3000 mg/day. An absolute range for LEV Cu.serum and Cu.PBMC was 1.00-26.99 and 0.33-4.43 μg/mL, respectively. Unlike Cu.serum, the average four-month LEV Cu.PBMC displayed a significant positive correlation with clinical features and P-gp expression; where patients with higher LEV Cu.PBMC experienced less number of seizure/month, better cognition and quality of life, and had a more reduction in P-gp expression, but no significant correlation with LEV daily dose was observed. A therapeutic response threshold of ≥ 0.82 μg/mL for LEV Cu.PBMCwas perceived by using a receiver operating characteristic curve that related the number of seizure/month to the LEV Cu.PBMC. The validity of this therapeutic threshold was significant in contrast to LEV Cu.serum.
Conclusion: Levetiracetam PBMC concentration is a more sensitive biomarker for LEV efficacy and correlates better with clinical events than Cu.serum and could represent a novel tool for more precise LEV monitoring.
Keywords: HPLC; Intracellular; MoCA; P-glycoprotein; QOLIE-10; Therapeutic drug monitoring.
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