Population Pharmacokinetics and Pharmacodynamics of Norvancomycin in Children With Malignant Hematological Disease

Knowledge of pharmacokinetic (PK) behavior of norvancomycin (NVCM) in pediatric patients is lacking, which leads to empirical therapy in clinical practice. This study developed a population PK model of children aged 0‐15 years; 112 opportunistic samples in total from 90 children were analyzed. The stability and prediction of the final model were evaluated by goodness‐of‐fit plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. The PKs of NVCM in children was described by a 2‐compartment model with first‐order elimination along with body weight and estimated glomerular filtration rate as significant covariates on clearance. The population typical values of the PK parameters were as follows: clearance 0.12 L/kg/h, central compartment distribution volume 0.17 L/kg, peripheral compartment distribution volume 0.38 L/kg, and intercompartmental clearance 0.35 L/kg/h. Logistic analysis showed that the ratio of area under the concentration‐time curve over 24 hours (AUC0‐24) to minimum inhibitory concentration (MIC) had the strongest correlation with clinical efficacy, and at least 80% clinical efficiency could be achieved when AUC0‐24/MIC ≥ 221.06 was defined as the target. Monte Carlo simulation results suggested that a higher dose was required for this pediatric population in order to reach the target. The dosing regimen was optimized based on the final model. A population PK model of NVCM was first characterized in children with hematologic malignancy, and an evidence‐based approach for NVCM dosage individualization was provided.