Cystatin C as a new covariate to predict the renal elimination of drugs
Thomas, F.(1), S Séronie-Vivien(1), F Bouissou(2), M Tafani(2), JP Delord(1), L Gladieff(1), E Chatelut(1)
(1) EA3035, Institut Claudius-Regaud ;(2) Centre Hospitalier Universitaire, Toulouse, France
Objectives. 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 (GFR) by 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. Three successive studies were performed to assess the benefit of considering cysC to predict GFR in children, carboplatin and topotecan clearances both in adults.
Patients and methods: For GFR estimation, 51Cr-EDTA clearance was determined for 100 children. The study of drugs clearance included 45 patients that were receiving carboplatin and 59 patients receiving topotecan 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 to create a model building data set (for screening the relationships between patients’ covariates and CL) and a model validation data set (for prospective evaluation of these relationships).
Results: For GFR estimation, Scr (serum creatinine), CysC (serum cystatine C), BW (body weight) and age were retained in the final model. Correlation between the GFR estimated by this covariates equation and actual values (r²=0.72, bias=+5.1%, precision=18 %) was less biased and more precise than that using the Schwartz [1] formula (r²=0.60, bias=+12.7%, precision=24.8%). For carboplatin, the best covariate equation was: CL(mL/min) = 110.(SCr/75)-0.512.(cysC/1.0)-0.327.(BW/65)0.474.(AGE/56)-0.387.[0.854SEX], with SEX = 0 if male, =1 if female. This model was significantly better (p<0.02) than that without cysC [2]. For topotecan, the best model included cysC and IBW (Ideal Body Weight) as covariates and shows a significantly (p<0.01) better predictive value than that based on SCr and IBW [3].
Conclusion: These three applications show that considering cysC results in a better clearance prediction than the current methods. CysC needs further exploration as a promising covariate for drug dosing.
References:
1. Schwartz GJ, Brion LP, Spitzer A. Pediatr Clin North Am 34:571-590, 1987
2. Thomas F, Seronie-Vivien S, Gladieff L et al. Clin Pharmacokinet 44:1305-1316, 2005
3. Hoppe A, Seronie-Vivien S, Thomas F et al. Clin Cancer Res 11:3038-3044, 2005
