Comparative Evaluation of the Cockcroft-Gault Equation and the Modification of Diet in Renal Disease (MDRD) Study Equation for Drug Dosing

An Opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy

Heather A. Nyman, Pharm.D.; Thomas C. Dowling, Pharm.D., Ph.D. FCCP; Joanna Q. Hudson, Pharm.D., FCCP; Wendy L. St. Peter, Pharm.D., FCCP; Melanie S. Joy, Pharm.D., Ph.D., FCCP; Thomas D. Nolin, Pharm.D., Ph.D., FCCP

Disclosures

Pharmacotherapy. 2011;31(11):1130-1144. 

In This Article

Abstract and Introduction

Abstract

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturerrecommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10–40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.

Introduction

The goal of dose individualization in patients with impaired kidney function is to maximize the likelihood that target drug concentrations will be achieved and thereby lead to an optimal therapeutic outcome. Calculation of estimated creatinine clearance (Clcr) by using the Cockcroft- Gault (CG) equation (Figure 1)[1–4] has been the most commonly used method to estimate kidney function for drug dosing purposes for decades. This approach stems partly from prospective pharmacokinetic studies often conducted during drug development that are designed to establish the relationship between drug elimination and kidney function (usually Clcr), according to the 1998 United States Food and Drug Administration (FDA) guidance pertaining to pharmacokinetic studies in patients with impaired kidney function.[5] In recent years, several new equations have been proposed to estimate kidney function in patients with chronic kidney disease (CKD).[6–8] In 2009, the National Kidney Disease Education Program (NKDEP), an initiative of the National Institutes of Health, updated its recommendations regarding drug prescribing to state that either the CG equation or the Modification of Diet in Renal Disease (MDRD) study equation (Figure 1) can be used as the estimate of kidney function for drug dosing.[4] In addition, the FDA has recently proposed that the MDRD equation be incorporated, in addition to the CG equation, into future pharmacokinetic studies in patients with kidney disease, and that pharmacokinetic results be shown for both estimates of kidney function.[9,10] Others have suggested that CG should remain the equation of choice for drug dosing, which has led to considerable debate on the topic.[11–15]

Figure 1.

Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) study equations and associated calculations.1–4 Clcr = estimated creatinine clearance; Scr = serum creatinine concentration (mg/dl); IBW = ideal body weight; TBW = total body weight; eGFR = estimated glomerular filtration rate; BSA = body surface area; IND = individualized.

There are many important factors to consider when assessing studies comparing the performance of the CG and MDRD equations for drug dosing. These factors include the weight used in the CG equation, the adjustment for body surface area (BSA) in the MDRD equation, the use of a standardized serum creatinine concentration, and the methods used in the original pharmacokinetic studies from which dosage recommendations for the drugs being studied were derived. The current lack of prospective pharmacokinetic data and dosing recommendations generated with use of the MDRD equation creates further challenges. In addition, the limitations and the study population of the original trials from which the estimating equations were developed must be considered before applying either equation to a specific patient.

In response to the continued controversy surrounding use of the MDRD equation to dose drugs in patients with impaired kidney function, in this article, the American College of Clinical Pharmacy (ACCP) Nephrology Practice and Research Network (PRN) presents the strengths and limitations of using each method to determine drug dosages. In addition, the implications of creatinine standardization are reviewed, and limitations of applying the CG and MDRD equations to select populations are outlined. Finally, an algorithm is proposed for using creatinine-based kidney function assessments in drug dosing.

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