Pharmacokinetics of Vancomycin in Pediatric Patients Receiving Intermittent Hemodialysis or Hemodiafiltration

Abstract

Introduction: Vancomycin is a common antibiotic used to treat hemodialysis (HD) or hemodiafiltration (HDF)-related infections in pediatric patients, but optimal dosing remains unknown. This is the first observational study to characterize the pharmacokinetics and evaluate dosing of vancomycin in this population.

Methods: Eligible patients received IV vancomycin 10 mg/kg per dose postdialysis followed by a series of serum vancomycin concentrations collected before, immediately after, 1 hour after, and 4 hours after dialysis. The pharmacokinetic parameters were estimated using 1- and 2-compartment models and a nonlinear least-squares algorithm.

Results: Among 42 vancomycin courses in 16 patients, 1 compartment model had the best fit for observed data. The net drug removal was 43 ± 13% (39% for HD and 50% for HDF) from an average 3-hour HD/HDF session. The mean elimination constant was 0.28 h^-1 (standard deviation [SD], 0.11 h^-1) during the intradialytic period compared with 0.0049 h^-1 (SD, 0.004 h^-1) when off dialysis. The mean volume of distribution was 0.65 (SD, 0.19) L/kg. Duration of dialysis session and mode of dialysis (HD vs. HDF) were significant predictors of vancomycin pharmacokinetic parameters. Half-life was shorter for HDF compared with HD (2.1 vs. 3.5 hours).

Conclusions: Based on the simulations, an initial vancomycin dose of 10 mg/kg per dose and redosing postdialysis was optimal to achieve a vancomycin concentration range of 5 to 12 mg/L at 4 hours postdialysis and 24-hour area under the curve over minimum inhibitory concentration of ≥400 hours. Therapeutic drug monitoring is necessary to account for residual variability in vancomycin elimination in pediatric patients receiving HD/HDF.

Keywords: dialysis; drug excretion; pediatrics; pharmacokinetics; vancomycin.

Graphical abstract

Figure 1

Screening for study inclusion.

Figure 2

Individual serum vancomycin concentration-time plots for nine individual vancomycin courses with at least 4 serum vancomycin concentrations collected pre-, immediately-post-, 1-hour-post-, and 4-hour-post-dialysis (a‒i). The final one-compartment pharmacokinetic model (blue line) was derived from optimization of elimination constants during intradialytic and interdialytic periods and volume of distribution using generalized reduced gradient method to minimize residual sum of squares from the initial model (dotted green line). Red circles represent observed serum vancomycin concentrations. Gray circles with orange dashed lines represent start and stop time of dialysis session. Yellow triangles represent doses given. HD, hemodialysis; HDF, hemodiafiltration.

Figure 3

Probability distribution of predicted 4-hour post-dialysis concentration and 24-h area under the concentration-time curve to minimal inhibitory concentration ratio (AUC/MIC) for pathogens with MIC = 0.5 mg/L after first dose and at steady state (after seventh dose) from dosing regimen of 10 mg/kg/dose IV every 2 days for daily 3-hour dialysis sessions.

Figure 4

Final model of mean serum vancomycin concentration‒time profile simulated with a vancomycin dosing regimen of 10 mg/kg/dose IV every 2 days (for 3 or 4 dialysis sessions per week). Orange dashed lines represent start and stop time for each dialysis session.

Figure 5

Vancomycin dosing and therapeutic drug monitoring guideline for pediatric patients receiving hemodialysis or hemodiafiltration. CNS, central nervous system; HD, hemodialysis; HDF, hemodiafiltration.