Development and validation of a clinical nomogram for predicting suboptimal concentration of valproate in pediatric...

Valproate, a first-line anti-seizure medication, has a narrow therapeutic range of 50-100 μg/mL. Many children are prescribed insufficient doses of valproate, resulting in inadequate seizure control or potential toxicity. Currently, no predictive algorithms are available to customize treatment according to the specific needs of children. Our objective was to develop a nomogram that predicts the likelihood of suboptimal valproate concentrations in pediatric patients with epilepsy.

We conducted a single-center retrospective cohort study of pediatric patients with epilepsy aged 2-18 years who were receiving valproate and had steady-state trough concentrations. The primary outcome was the identification of suboptimal valproate concentrations, defined as levels below 50 μg/mL or above 100 μg/mL. The Boruta algorithm was implemented to identify relevant characteristics from demographic, clinical, and pharmacological variables. Significant predictors identified through this process were incorporated into a multivariable logistic regression model, which was subsequently presented as a nomogram. We assessed the model's performance regarding discrimination using the area under the curve (AUC) and concordance index (C-index), calibration through a calibration plot and the Hosmer-Lemeshow test, and clinical value via decision curve analysis to guarantee robustness. Bootstrap resampling was performed for internal validation.

Among the 121 included patients,38 (31.4%) patients presented with suboptimal concentrations. The Boruta algorithm and multivariate regression analysis identified four predictors: daily valproate dose (mg/kg/d), acute liver injury (ALI), acute kidney injury (AKI), and the concurrent use of meropenem. The model showed excellent discrimination with an AUC of 0.911 (95% CI 0.849-0.974) and an optimism-corrected C-index of 0.902, alongside good calibration. Decision curves showed a clinical net benefit over a broad probability threshold range (3%-99%). AKI (odds ratio [OR] 16.5), meropenem use (OR 17.39), and ALI (OR 10.86) were significantly associated with suboptimal concentrations.

We developed and internally validated a predictive nomogram that integrates dose, AKI, ALI, and meropenem use to assess the risk of suboptimal concentrations of valproate in pediatric epilepsy. This tool can aid in the early identification of high-risk patients, enabling targeted therapeutic drug monitoring.