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

Abstract

PURPOSE In overweight patients, the Cockcroft-Gault (CG) formula is more likely to overestimate renal function and carboplatin dosing. In this prospective pharmacokinetic study, we evaluated the use of an adjusted Cockcroft-Gault formula (aCG) correcting, amongst other things, for overweight. METHODS aCG adjusted in patients with BMI > 25 kg/m² using adjusted ideal body weight, capping low serum creatinine values at 60 µmol/L, and high creatinine clearance values at 125 mL/min. Patients were categorized: BMI < 25.0 (normal weight), 25.0–29.9 (overweight), and ≥ 30.0 kg/m² (obese). To assess pharmacokinetics, blood samples were taken and carboplatin ultrafiltrate concentrations were analyzed. Exposure was estimated using a population pharmacokinetic model and compared to the target AUC regarding bias (Mean Prediction Error, MPE%) and imprecision (Mean Absolute Prediction Error, MAPE%). Additionally, substitutes for renal function, including additional weight descriptors, cystatin C, 24-hour creatinine clearance, and estimators of GFR were compared. RESULTS Eighteen patients were included. aCG slightly underestimated the estimated AUC across all weight groups, with the highest deviation in obese patients (MPE%: -10.5%) versus 8.8% using CG. aCG underestimated in normal and overweight of -5.7% and 1.1% compared to -4.2% and 2.8% using CG. The most accurate predictor of target AUC for all weight categories was cystatin C (MPE%: +0.2%, -2.0 and − 0.1% for normal, overweight, and obese patients respectively) with low imprecision (MAPE%: 9.8%, 9.5%, and 13.3%). CONCLUSION This study could not find evidence to support using our aCG to better predict carboplatin clearance compared to CG. Cystatin C showed to be the most precise and accurate biomarker for carboplatin clearance.