Cystatin C as a new covariate to predict the elimination of drugs: Application to carboplatin and topotecan

Abstract

2029 Background: Individual dosing of drugs mainly eliminated by renal excretion is possible by estimation of the renal function. Most of the methods aim to assess the glomerular filtration rate using the creatinine clearance based on the serum creatinine level (SCr). Recently, serum cystatin C (cysC) has been proposed as an alternative endogenous marker of glomerular filtration rate. The purpose of this study was to assess cysC as a predictor of carboplatin and topotecan clearances (CL), drugs for which SCr was shown as a significant covariate to decrease the interindividual variability. Methods: Patients were receiving carboplatin (45 patients) or topotecan (59 patients) as part of established protocols. Their plasma concentrations versus time were analyzed according to a population pharmacokinetic approach using NONMEM program. Data-splitting was randomly done for both drugs to create a model building data set (for screening the relationships between morphologic, biological and demographic covariates and CL) and a model validation data set (for prospective evaluation of these relationships). Results: For carboplatin, the best covariate equation (± 95% Confidence Interval) was: CL (mL/min) = 110(±10.5). [ (SCr/75)−0.512(±0.255)]. [ (cysC/1.0)−0.327(±0.184)]. [ (BW/65)0.474(±0.223)]. [ (AGE/56)−0.387(±0.123)]. [0.854(± 0.099)SEX], with SCr in μmol/L, cysC in mg/L, BW (Body Weight) in kg, and SEX = 0 if male, =1 if female. This model was significantly better (p<0.02) than that without cysC. For topotecan, the best model included cysC and IBW (Ideal Body Weight) as covariates: CL (L/h) = 19.7(±1.3). (cysC/1.06)−0.61(±0.20). (IBW/57)0.93(± 0.58). This model had a significantly (p<0.01) better predictive value than that based on SCr and IBW. Conclusion: For both drugs, considering cysC results in a better clearance prediction than the current Methods: CysC needs further exploration as a promising covariate for drug dosing. No significant financial relationships to disclose.