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

Authors' Affiliation: EA 3035 and Department of Clinical Biology, Institut Claudius-Regaud, Toulouse, France

Requests for reprints: Etienne Chatelut, Institut Claudius-Regaud, F-31052 Toulouse, France. Phone: 33-561-42-4271; Fax: 33-561-42-4631; E-mail: chatelut{at}icr.fnclcc.fr.

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]^–0.60 [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.

Key Words: Population pharmacokinetics • individual dosing • renal function

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