Serum Cystatin C is a Better Marker of Topotecan Clearance than Serum Creatinine

Abstract

Purpose: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics.Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance. Experimental Design: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients).Results: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06] À0.60 [IBW (kg) / 57] 0.95 . Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area. Conclusion: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.

Augmented Renal Clearance Implies a Need for Increased Amoxicillin-Clavulanic Acid Dosing in Critically Ill Children

“…Second, it has been shown that CysC is a good renal biomarker in children with sepsis (28) and that CysC-based GFR estimations remain accurate in children presenting with hyperfiltration (in contrast to Scr-based formulae) (24). Finally, CysC was found to better predict elimination of renally excreted drugs in adults compared to Scr or CrCL (29)(30)(31)(32). This is only the second report to identify this new biomarker as a predictor of renal drug clearance in children at the expense of Scr or CrCL (33).…”

Cystatin C: current position and future prospects

“…It concluded that this new parameter was not superior to creatinine in predicting drug clearance. However, these results were rapidly refuted (261) and two studies based on population pharmacokinetics methodology, the most robust in this field, definitively demonstrated the utility of CysC in predicting the clearance of drugs which were eliminated either exclusively or only partially by the kidneys, i.e., two cytotoxic agents, topotecan (262) and carboplatin (263). Interestingly, both of these studies showed an advantage of combining CysC with creatinine rather than using either individually.…”

A Universal Formula Based on Cystatin C to Perform Individual Dosing of Carboplatin in Normal Weight, Underweight, and Obese Patients

“…We recommend the use of the particle-enhanced nephelometric immunoassay or particle-enhanced turbidimetric immunoassay method to determine cysC for individual carboplatin dosing. Lastly, because carboplatin elimination is highly dependent on renal function, the benefit of considering cysC for individual dosing should also exist for other renally cleared drugs such as topotecan in Oncology (23), and aminoglycosides in Infectious Diseases (24).…”