Pharmacokinetic study of carboplatin using various overweight-correcting dosing algorithms and biomarkers in patients with varying BMI categories

Abstract

Background: The Cockcroft-Gault (CG) formula is more likely to overestimate renal function and carboplatin dosing in patients who are overweight. In this prospective pharmacokinetic study, the use of an adjusted Cockcroft-Gault formula (aCG) was evaluated to correct for overweight status. Methods: aCG was adjusted in patients with body mass index (BMI) >25 kg/m(2) using adjusted ideal body weight, capping low serum creatinine values at 60 mu mol/L, and high creatinine clearance values at 125 mL/min. Patients were categorized as follows: BMI <25.0 (normal weight), 25.0-29.9 (overweight), and >= 30.0 kg/m(2) (obese). To assess the pharmacokinetics, blood samples were collected and carboplatin ultrafiltrate concentrations were analyzed. Exposure was estimated using a population pharmacokinetic model and compared with the target area under the curve (AUC) regarding bias mean prediction error (MPE%) and imprecision mean absolute prediction error (MAPE%). In addition, substitutes for renal function, including weight descriptors, cystatin C, 24-hour creatinine clearance, and glomerular filtration rate estimators, were compared. Results: Eighteen patients were included in this study. aCG slightly underestimated individual carboplatin clearance across all weight groups, with the highest deviation in patients who had obesity (MPE%: -10.5%) versus +8.8% using CG. aCG underestimated -5.7% in patients with a normal weight and overestimated by +1.1% in those who were overweight, compared with -4.2% and +2.8%, respectively, using CG. The most accurate predictor of the target AUC for all weight categories was cystatin C (MPE%: +0.2%, -2.0%, and -0.1% for patients with a normal weight, those who were overweight, and those who had obesity, respectively) with low imprecision (MAPE%: 9.8%, 9.5%, and 13.3%, respectively). Conclusions: This study did not find evidence to support using aCG to predict carboplatin clearance better than CG. However, cystatin C was found to be the most precise and accurate biomarker for carboplatin clearance.