title: Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency.
abstract: BACKGROUND
  Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.
  
  
  METHODS
  Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.
  
  
  RESULTS
  Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.
  
  
  CONCLUSIONS
  Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.
authors.affiliation: University of California San Diego, La Jolla, CA ; Miller Children's Hospital, Long Beach, CA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Le
authors.affiliation: University of California San Diego, La Jolla, CA.
authors.forename: Florin
authors.initials: F
authors.lastname: Vaida
authors.affiliation: Miller Children's Hospital, Long Beach, CA.
authors.forename: Emily
authors.initials: E
authors.lastname: Nguyen
authors.affiliation: Children's Hospital of Orange County, Orange, CA.
authors.forename: Felice C
authors.initials: FC
authors.lastname: Adler-Shohet
authors.affiliation: University of California San Diego, La Jolla, CA.
authors.forename: Gale
authors.initials: G
authors.lastname: Romanowski
authors.affiliation: Rady Children's Hospital, San Diego, CA.
authors.forename: Jiah
authors.initials: J
authors.lastname: Kim
authors.affiliation: Miller Children's Hospital, Long Beach, CA.
authors.forename: Tiana
authors.initials: T
authors.lastname: Vo
authors.affiliation: University of California San Diego, La Jolla, CA.
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
keywords: Antibiotic; Antibiotic resistance; Area-under-the curve; Children; Methicillin-resistant Staphylococcus aureus (MRSA); Monte Carlo simulation; Pediatrics; Pharmacokinetic-pharmacodynamic; Population-based pharmacokinetic modeling; Renal disease; Renal insufficiency; Staphylococcus aureus; Vancomycin