Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters.

Abstract

Simple SummaryCarboplatin is a chemotherapeutic agent that is usually dosed based on body surface area or weight. However, carboplatin is cleared from the body by the kidneys. Therefore, taking the patient’s kidney function into account to calculate the adequate dose of carboplatin might result in a better exposure of carboplatin within a patient. In this study we sought to validate a carboplatin dosing method based on kidney function and compare several methods for kidney function-based carboplatin dosing in children suffering from retinoblastoma. We were able to show that carboplatin dosing based on a marker of kidney function (cystatin C) resulted in more adequate dosing than dosing on body surface area or weight.Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3–89.5% versus 76.3–78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.