Population Pharmacokinetics and Dosing Optimization of Vancomycin in Infants, Children, and Adolescents with Augmented Renal Clearance.

ABSTRACT

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in a pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range, 0.4 to 14.9 years; 49 females and 64 males) were available. The mean vancomycin dose was 58.8 mg/kg body weight/day (13.6 mg/kg/dose), and the mean vancomycin serum trough concentration was 6.5 mg/liter. A one-compartment pharmacokinetic model with first-order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. For the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) ratio of 400 to 700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month to 18 years.