External Evaluation of Population Pharmacokinetic Models of Vancomycin in Large Cohorts of Intensive Care Unit Patients

Abstract

Dosing of vancomycin is often guided by therapeutic drug monitoring and population pharmacokinetic models in the intensive care unit (ICU). The validity of these models is crucial, as ICU patients have marked pharmacokinetic variability. Therefore, we set out to evaluate the predictive performance of published population pharmacokinetic models of vancomycin in ICU patients. The PubMed database was used to search for population pharmacokinetic models of vancomycin in adult ICU patients. The identified models were evaluated in two independent data sets which were collected from two large hospitals in the Netherlands (Amsterdam UMC, Location VUmc, and OLVG Oost). We also tested a one-compartment model with fixed values for clearance and volume of distribution, in which a clinical standard dosage regimen (SDR) was mimicked to assess its predictive performance. Prediction error was calculated to assess the predictive performance of the models. Six models plus the SDR model were evaluated. The model of Roberts et al. (J. A. Roberts, F. S. Taccone, A. A. Udy, J.-L. Vincent, F. Jacobs, and J. Lipman, Antimicrob Agents Chemother 55:2704-2709, 2011, https://doi.org/10.1128/AAC.01708-10) performed satisfactorily, with mean and median values of prediction error of 5.1% and -7.5%, respectively, for Amsterdam UMC, Location VUmc, patients, and -12.6% and -17.2% respectively, for OLVG Oost patients. The other models, including the SDR model, yielded high mean values (-49.7% to 87.7%) and median values (-56.1% to 66.1%) for both populations. In conclusion, only the model of Roberts et al. was able to validly predict the concentrations of vancomycin for our data, whereas other models and standard dosing were largely inadequate. Extensive evaluation should precede the adoption of any model in clinical practice for ICU patients.

Keywords: ICU patients; NONMEM; antibiotics; model validation; population pharmacokinetics; vancomycin.

FIG 1

Box plot of the prediction error (in percent) of the evaluated models with VUmc patients (left) and OLVG patients (right). The bold solid lines within each box are the median values. The lower and upper limits of the box are the first and third quartiles. The red dashed lines are ±20% of the prediction error. SDR is the standard dosage regimen model.

FIG 2

Bland-Altman plot of published models based on the VUmc data set. Red dashed lines are the mean and mean ± 1.96 times the SD of the prediction error. Pred, predicted; Obs, observed.

FIG 3

Bland-Altman plot of published models based on the OLVG data set. Red dashed lines are the mean and mean ± 1.96 times the SD of the prediction error. Pred, predicted; Obs, observed.