Population pharmacokinetics and dosing optimization of vancomycin in children with malignant hematological disease

Abstract

An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (Css/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target Css/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Model evaluation. (A and B) Routine diagnostic goodness-of-fit plots: population predicted (PRED) versus observed concentrations (DV) and individual predicted (IPRED) versus observed concentrations (DV). (C and D) Conditional weighted residuals (CWRES) versus time and conditional weighted residuals (CWRES) versus population predicted concentrations (PRED). (E and F) Normalized prediction distribution errors (NPDE): Q-Q plot of the distribution of the NPDE versus the theoretical N(0, 1) distribution and a histogram of the distribution of the NPDE, with the density of the standard Gaussian distribution overlaid. (G) Visual predictive check (VPC). Circles represent the observed, while dashed lines depict the 5th and 95th percentiles of the simulated data. The solid lines indicate the median obtained from the simulated data. (H) Box plots of the distributions of observed (Obs) and predicted (Sim) Css/min values from 1,000 simulations. The bold horizontal bars in the middle show the median values of vancomycin Css/min values, while the outer boundaries of the boxes represent the ranges of the 25th and the 75th percentiles (interquartile ranges).

FIG 2

The relationship between vancomycin clearance and covariates. (A) Vancomycin clearance versus weight. (B) Vancomycin clearance (normalized by size) versus creatinine clearance. Size is defined as (body weight/20.2)0.677. Dashed lines depict the typical covariate-CL relationship.

FIG 3

Target attainment rates and fraction of patients above maximum recommended Css/min. The target attainment rates and fraction of patients above the maximum recommended C0 for the 100 simulated trials are presented as a function of dose and age group. The AUC/MIC target is 400 h; the MIC is 1 mg/liter. The maximum recommended Css/min is 20 mg/liter.

FIG 4

AUC and Css/min distribution. Simulated vancomycin AUC and Css/min distribution in infants and in children and adolescents receiving the mg/kg-basis dose and patient-tailored dose.