title: Improved vancomycin dosing in children using area under the curve exposure.
abstract: 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 * (0.48/serum creatinine) * (ln(age)/7.8) 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 ~75% and trough concentrations ≥15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~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 75% of patients.
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0714, USA. jenle@ucsd.edu
authors: Jennifer
authors: J
authors: Le
authors: John S
authors: JS
authors: Bradley
authors: William
authors: W
authors: Murray
authors: Gale L
authors: GL
authors: Romanowski
authors: Tu T
authors: TT
authors: Tran
authors: Natalie
authors: N
authors: Nguyen
authors: Susan
authors: S
authors: Cho
authors: Stephanie
authors: S
authors: Natale
authors: Ivilynn
authors: I
authors: Bui
authors: Tri M
authors: TM
authors: Tran
authors: Edmund V
authors: EV
authors: Capparelli
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D014640:Vancomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine