Population Pharmacokinetics of Intermittent Vancomycin in Children with Cystic Fibrosis

BACKGROUND Vancomycin is the drug-of-choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in children with cystic fibrosis. However, no studies have characterized the pharmacokinetic profile of vancomycin among pediatric cystic fibrosis patients. OBJECTIVE To evaluate the pharmacokinetics of intermittent vancomycin administration in children with cystic fibrosis and identify covariates that significantly influence vancomycin efficacy and safety. METHODS Therapeutic drug monitoring data were obtained from two cystic fibrosis care centers that identified children < 18 years who received vancomycin treatment for an acute pulmonary exacerbation from 2005 to 2010. Trough and peak serum concentrations were determined before and after the third or fourth dose. Nonlinear mixed effects models were developed to evaluate the population pharmacokinetics of vancomycin. RESULTS Among the 67 children (mean age 12.1 +/- 5.3 years), the mean vancomycin dose was 17.4 +/- 4.4 mg/kg. The mean trough concentration (C-min) was 10.3 +/- 3.8 mg/L. The mean daily area under the serum concentration time curve (AUC(24)) was 282.5 +/- 816.9 mg.hour/L. A one-compartment model with first-order elimination best described the data. Weight significantly influenced vancomycin clearance (p<0.001). In the final model, clearance was estimated as 5.57 L/hour/70 kg, and the volume of distribution was 44.1 L/70 kg. The between subject variability for clearance and volume of distribution were 27% and 40%, respectively. CONCLUSIONS Using a one-compartment model to evaluate the pharmacokinetic properties of vancomycin in children with cystic fibrosis, clearance increased with body weight. Pharmacodynamic studies are needed to establish an optimal vancomycin dosing regimen for the treatment of pediatric exacerbations of cystic fibrosis.