Improved Vancomycin Dosing in Children Using Area Under the Curve Exposure

Background: Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) >= 400 and trough concentration >= 15 mcg/mL. Methods: The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children >= 3 months old who received vancomycin for >= 48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed. Results: Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt(0.75) * (0.48/serum creatinine)(0.361) * (ln(age)/7.8)(0.995) and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39-52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects >= 12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in similar to 75% and trough concentrations >= 15 in similar to 45% of virtual subjects. An AUC/MIC similar to 400 corresponded to trough concentration similar to 8 to 9 mcg/mL. Conclusions: Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC >= 400 in similar to 75% of patients.