Comparison of equations for dosing of medications in renal impairment

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Chronic kidney disease (CKD) is a significant and growing public health problem that is associated with premature mortality.1 Renal impairment alters the effects of many drugs, sometimes decreasing their effects but more often increasing their effects and potentially toxicity.2 Many of these changes are predictable and can be prevented by adjusting drug doses.3 Traditionally, the creatinine clearance (CrCl) estimated by the Cockcroft‐Gault equation4 has been the most commonly used method to estimate renal function for drug dosing purposes, as evidenced by its widespread use in both drug developmental arenas and recommendations that appear in pharmaceutical product information.4
In recent years, several new equations have been proposed to estimate kidney function in patients with CKD; the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations.5 These latter equations, normalized for the patient's body surface area (BSA) and expressed in mL/min per 1.73 m2, are routinely used in Australian laboratories and health centres to automatically report eGFR with every request for serum creatinine determination.7 There is abundant evidence that these two new equations provide more accurate estimation of the GFR9; however, there has also been discussion on whether these new equations could be used for renal drug dosing.10
Studies have questioned the use of the Cockcroft‐Gault equation for renal dosing and recommended using MDRD for conducting renal pharmacokinetic studies and adjusting doses in the clinical settings.14 The Cockcroft‐Gault formula is prone to high variability because of inconsistent use of ideal, actual or adjusted body weight and indicates the need for dosage adjustment more often because of a more conservative estimation of kidney function.16
The United States National Kidney Disease Education Program stated that either the Cockcroft‐Gault or MDRD equation can be used as the estimate of kidney function for drug dosing.18 Similarly, in 2007 the Australasian Creatinine Consensus suggested that using the eGFR calculated with the MDRD formula was acceptable to assist with drug dosing decisions in general practice for non‐critical‐dose drugs.19 This has led to considerable debate on the topic,13 with some studies suggesting that Cockcroft‐Gault should remain the equation of choice for drug dosing as the differences in the doses rendered were too significant to replace Cockcroft‐Gault with MDRD for dosing.13
The CKD‐EPI equation has been recommended to be used in clinical laboratories to routinely provide eGFR values with each request for serum creatinine.26 There is, however, limited information on clinical application of this equation for the purpose of dose adjustment. Further, unlike MDRD, there has been no formal recommendation on use of this equation for drug dosing. However, it is worth noting that clinicians often use the eGFR provided by the laboratories for drug dosing purposes in the clinical setting.27
Given this background, we were interested to evaluate the agreement among the three formulae if hypothetically used in dosing of renally cleared drugs commonly prescribed in primary care settings. The two objectives of the study were to (i) compare kidney function estimates based on the CKD‐EPI, Cockcroft‐Gault and MDRD equations and (ii) determine the concordance among the Cockcroft‐Gault equation, MDRD (with and without BSA normalization) and the CKD‐EPI equation (with and without BSA normalization) for hypothetical dosing of renally cleared medications.
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