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

Abstract

Purpose: It has recently been shown that it is possible to improve the prediction of carboplatin clearance by adding plasma cystatin C level (cysC), an endogenous marker of glomerular filtration rate, to the other patient characteristics routinely used for carboplatin individual dosing, namely serum creatinine (Scr), actual body weight (ABW), age, and sex. This multicenter pharmacokinetic study was done to evaluate prospectively the benefit of using cysC for carboplatin individual dosing. Experimental Design: The 357 patients included in the study were receiving carboplatin as part of established protocols. A population pharmacokinetic analysis was done using NONMEM program. Seven covariates studied were as follows: Scr, cysC, age, sex, ABW, ideal body weight, and lean body mass. Using an alternative weight descriptor (ideal body weight or lean body mass) did not improve the prediction. This final covariate model was validated by bootstrap analysis. The bias (mean percentage error) and imprecision (mean absolute percentage error) were +1% and 15%, respectively, on the total population, and were of a similar magnitude in each of the three subgroups of patients defined according to their body mass index. Conclusion: For the first time, a unique formula is proposed for carboplatin individual dosing to patients, which is shown to be equally valid for underweight, normal weight, and obese patients. (2) using the measured creatinine clearance (CrCl; requiring 24-hour urine collection). Some years later, Calvert et al. (3) proposed to use the GFR measured by the clearance (CL) of [Cr 51 ]EDTA. Since then, substituting the CrCl calculated with the Cockcroft-Gault equation (4) into the Calvert formula (i.e., carboplatin CL = CrCl + 25) is the most widely used method to calculate the individual dose of carboplatin. Over the past 15 years, there has been an endless debate concerning the best equation to predict carboplatin CL. No single equation has been found to be applicable to all patients without bias except for the original method based on [Cr 51 ]EDTA CL determination (5). The main limitation of the existing equations is that they are all based on serum creatinine level (Scr) as the unique biological covariate (together with demographical and morphologic covariates). Scr is dependent on GFR, but its rate of production depends on muscle mass. Because of this, it has been shown that several of the existing formulae overestimate carboplatin CL in both obese patients and patients with cachexia (6). Recently, Thomas et al. (7) showed by analyzing the pharmacokinetic data of 45 patients from one center that cystatin C plasma level (cysC) was a marker of carboplatin elimination that is at least

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“…This situation might be a source of confusion, especially for residents used to working in different departments. Moreover, the conference highlighted a population at risk of carboplatin overdose: cachectic or obese patients for which the Thomas formula would be more suitable [31]. A decision tree was drawn up for selecting the best formula among the Chatelut, Thomas and Calvert ones.…”

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“…Although CrCl can be estimated with any of the existing formulas, since CrCl correlates with BSA, it seems reasonable to avoid the use of the Jelliffe formula in obese patients since it may result in unnecessary dose reductions. Schmitt and colleagues have proposed a unique formula, using cystatin C, an endogenous marker of GFR that has been shown to be an equally valid predictor of individual dosing of carboplatin in underweight, normal weight, and obese patients [18]. …”

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“…However, as these equations are based on estimation serum creatinine level, they tend to overestimate creatinine clearance in obese patients [9]. The Cockroft-Gault equation, which is the most frequently used to estimate creatinine clearance in Calvert formula, is no exception.…”