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

• Published in: Clinical cancer research 2009-05, Vol.15 (10), p.3633-3639
• Main Authors: SCHMITT, Antonin, GLADIEFF, Laurence, LE GUELLEC, Chantal, PENEL, Nicolas, CAMPONE, Mario, LARGILLIER, Rémy, CAPITAIN, Olivier, FABBRO, Michel, HOUEDE, Nadine, MEDIONI, Jacques, BOUGNOUX, Philippe, LOCHON, Isabelle, LANSIAUX, Amélie, CHATELUT, Etienne, BOBIN-DUBIGEON, Christine, ETIENNE-GRIMALDI, Marie-Christine, BOISDRON-CELLE, Michèle, SERRE-DEBAUVAIS, Françoise, PINGUET, Frédéric, FLOQUET, Anne, BILLAUD, Eliane
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Analysis of Variance; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Body Mass Index; Body Weight - physiology; carboplatin; Carboplatin - administration & dosage; Carboplatin - pharmacokinetics; Carboplatin - therapeutic use; Cystatin C - blood; Dose-Response Relationship, Drug; Female; Humans; Immunoassay - methods; individual dosing; Male; Medical sciences; Metabolic Clearance Rate; Metabolic diseases; Middle Aged; Models, Biological; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - physiopathology; Obesity; Obesity - physiopathology; pharmacokinetics; Pharmacology. Drug treatments; Prospective Studies; Reproducibility of Results; Tissue Distribution; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-0017

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. Results: The best covariate equation was as follows: carboplatin clearance (mL/min) = 117.8. (Scr/75) −0.450 . (cysC/1,00) −0.385 . (ABW/65) +0.504 . (age/56) −0.366 . 0.847 sex , with Scr in μmol/L, cysC in mg/L, ABW in kilograms, age in years, and sex = 0 for male. 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.