Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function

We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoek''s formula correlated linearly with VAN clearance (VAN clearance ml/min] = 0.825 × GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (−3.45 to −1.38) of the difference in each value of the mean absolute error (−2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.Vancomycin (VAN) has been widely used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. It is mainly eliminated via the kidneys and has a narrow therapeutic range; high doses cause nephrotoxicity, particularly if it is used in combination with an aminoglycoside antibiotic (6, 28). The area under the blood concentration-time curve (AUC)/MIC is the pharmacodynamic parameter that best correlates with a successful outcome after the use of VAN (20, 27). Therefore, it is believed that therapeutic drug monitoring (TDM) is appropriate for VAN therapy (3, 16, 18, 29).The initial VAN dosage regimen is usually selected by use of a nomogram that uses the serum creatinine concentration as a marker of renal function. Our previous studies indicated that the nomogram that uses the serum creatinine concentration does not accurately predict the serum VAN trough concentration, particularly in elderly individuals (33). This is probably caused by using the serum creatinine concentration as a marker of renal function because this leads to an overestimation of the glomerular filtration rate (GFR) (17). A more accurate marker of GFR is needed for the appropriate use of VAN because renal function is one of the most important factors affecting the clearance of VAN.It has been reported that the serum cystatin C concentration is a better marker of renal function than the serum creatinine concentration (5). A recent meta-analysis demonstrated that the serum cystatin C concentration is superior to the serum creatinine concentration for use for the detection of an impaired GFR (7). Some studies reported that the serum cystatin C concentration is a better marker of drug clearance than the serum creatinine concentration (15, 23). Recently, we have shown that the serum cystatin C concentration is a better marker for determination of the initial dose in VAN therapy. In a previous study, GFR was estimated on the basis of the serum cystatin C concentration in place of the creatinine clearance, which is the parameter usually used to determine the population pharmacokinetics of VAN (32). However, a means of population pharmacokinetic analysis that uses the serum cystatin C concentration as a marker of renal function is lacking.We approached the population pharmacokinetic analysis of VAN using the serum cystatin C concentration and a one-compartment model for adult patients infected with MRSA. Covariate selection revealed that total body weight (TBW) affected the volume of distribution, whereas renal function (estimated from GFR by use of the serum cystatin C concentration) affected VAN clearance. We also compared the predictive performance of the trough serum VAN concentration for determination of the initial dose with that of the use of the nomogram and the serum creatinine concentration.