A Population Pharmacokinetic Model for Cr EDTA to Estimate Renal Function.

BACKGROUND AND OBJECTIVES

Cr EDTA clearance (CL) from plasma is used to estimate glomerular filtration rate (GFR). We propose that current methods for analysing the raw Cr EDTA measurements over-simplifies the disposition of Cr EDTA and therefore could produce biased GFR estimates. The aim of this study was to develop a population pharmacokinetic model for Cr EDTA disposition and to compare model-predicted GFR to other methods of estimating renal function.

PATIENTS AND METHODS

Data from 40 individuals who received ~7.4 MBq of Cr EDTA, as an intravenous bolus, were available for analysis. Plasma radioactivity (counts/min) was measured from timed collection points at 2, 4, 6 and 24 h after the dose. A population analysis was conducted using NONMEM version 7.2. Model-predicted GFR was compared with other methods for estimating renal function using mean prediction error (MPE).

RESULTS

A two-compartment pharmacokinetic model with first-order elimination best fit the data. Compared with the model predictions, creatinine CL from 24 h urine data was unbiased. The commonly used 'slope-intercept' method for estimating isotopic GFR was positively biased compared with the model (MPE 15.5 mL/min/1.73 m [95% confidence interval {CI} 8.9-22.2]. The Cockcroft Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equations led to negatively biased GFR estimates (MPE -19.0 [95% CI -25.4 to -12.7], -20.1 [95% CI -27.2 to -13.1] and -16.5 [95% CI -22.2 to -10.1] mL/min/1.73 m, respectively).

CONCLUSIONS

The biased GFR estimates were most obvious in patients with relatively normal renal function. This may lead to inaccurate dosing in patients who are receiving drugs with a narrow therapeutic range where dosing is adjusted according to GFR estimates (e.g. carboplatin).

STUDY REGISTRATION

The study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number: ACTRN 12611000035921.