Abstract
BACKGROUND: This study sought to define the therapeutic drug monitoring (TDM) reference range and assess the efficacy-safety profile along with its determinants for levetiracetam (LEV) in Chinese children with epilepsy. METHODS: We conducted a retrospective study (2021-2023) at Children's Hospital of Nanjing Medical University in children with epilepsy taking LEV therapy with routine TDM. The observational LEV reference range was defined by the generalized additive models for location, scale, and shape (GAMLSS) analysis. A linear mixed-effects model identified concentration determinants. Efficacy was assessed via propensity score matching (PSM)-adjusted logistic regression, time-to-failure via Kaplan-Meier/Cox regression (monotherapy), and adverse events (AEs) temporal patterns via Weibull distribution analysis. RESULTS: This study (n = 1,174) proposed an observational LEV reference range of 2.82-24.37 µg/mL based on the 2.5th-97.5th percentile distribution. Predictors of LEV levels included age, body weight, oxcarbazepine (OXC)/topiramate use, and developmental delay. OXC lowered concentration-to-dose (C (0)/D) (β = -0.1824, P = 0.0012). The 12-month response rate was 81.01% (90.89% monotherapy vs 70.78% polytherapy). Concentration-response correlation was significant only in focal epilepsy. Protective factors for response were female sex, generalized epilepsy, and longer treatment; risk factors were polytherapy and infectious etiology. Comorbid attention deficit and hyperactive disorder improved, but developmental delay did not affect, response. Neuropsychiatric AEs were most frequent (median onset: 196.5 days); gastrointestinal and systemic reactions showed early failure patterns. CONCLUSION: This real-world study confirmed the efficacy and safety of LEV in Chinese children with epilepsy and revealed relevant drug interactions. By proposing an observational LEV reference range (2.82-24.37 µg/mL), it provides a critical evidence base for TDM and guides the personalized treatment.