Serum cystatin C is a major predictor of vancomycin clearance in a population pharmacokinetic analysis of patients with normal serum creatinine concentrations

Abstract

We developed a population pharmacokinetic model of vancomycin by integrating the effects of cystatin C and other demographic factors in a large population of Korean patients with normal serum creatinine concentrations to elucidate the precise role of serum cystatin C concentrations in the prediction of vancomycin clearance. A population pharmacokinetic model of vancomycin was developed using NONMEM software from a total of 1,373 vancomycin concentration measurements in 678 patients whose serum creatinine concentrations were lower than 1.2 mg/dL. Covariate selection revealed that cystatin C was the most influential factor and had negative influence ((-0.78)) in the relationship. Total body weight, sex, age, and serum creatinine were also significantly correlated with the clearance. The estimated intersubject variabilities of clearance and volume of distribution were 24.7% and 25.1%, respectively. A 14-fold difference in predicted trough concentrations was observed according to only cystatin C concentrations in a population of simulated individuals with median demographic characteristics. The use of serum cystatin C as marker of vancomycin clearance for more accurate predictions of serum vancomycin concentrations could be useful, particularly among patients with normal serum creatinine concentrations.

Keywords: Cystatin C; NONMEM; Pharmacokinetics; TDM; Vancomycin.

Fig. 1

Goodness of fit evaluated by the plots of (A) population prediction versus observed vancomycin concentration (mg/L) and (B) individual prediction versus observed vancomycin concentration (mg/L). Solid lines are the linear regression line from the data (thick) or the line of identity (thin).

Fig. 2

Results of the numerical predictive check. The connected black dots represent the ratio of the number of observations that are outside their own prediction intervals to the expected number (e.g., 10% of the data are expected to be outside a 90% prediction interval, 5% above and 5% below). The dotted lines represent the 95% confidence intervals for this ratio given the correct model.

Fig. 3

Predicted steady-state vancomycin concentration during and after the administration of 1,000 mg of vancomycin q 12 hr when only cystatin C changed in patients with typical demographic characteristics (A) and in representative patients with low (CL = 1.7 L/h and V = 41.8 L) or high (C L= 10.9 L/h and V = 45.7 L) vancomycin clearance calculated by their covariates (B).