Remembering the Past

TO THE EDITOR: In a recent publication, Brown et al. suggests using a functional creatinine clearance (CrCl) range to guide drug dosage adjustment for renally eliminated drugs. This range uses an upper and lower uncorrected CrCl estimate (mL/min) that is calculated from the Cockcroft-Gault (CG) equation using ideal body weight and total body weight respectively. Other investigators have also evaluated several weight relationships and adjustment factors to determine which approach optimizes the predictive performance of this equation. In the midst of these ongoing efforts, it is instructional for practitioners to recall some of the earlier literature that has expressed concern with using weight in the CG calculation to derive an uncorrected CrCl (mL/min) for the purpose of renal drug dosage adjustment. In 1976, Hull and Sarubbi published a nomogram that determined gentamicin dosage using a CrCl that was derived from age, weight, and serum creatinine (SCr). A subsequent commentary questioned the ability of this nomogram to accurately calculate maintenance doses for large or small patients based on the observation that the CrCl was not corrected to body size (uncorrected). Spyker and Guerrant emphasized that the frequency of drug administration or dosage interval depends not only on renal function (clearance) but also on distribution volume (Vd), which together determine drug half-life. The uncorrected CrCl would address clearance (CL) but would not account for Vd, which also influences the rate of drug elimination (Ke) indicated by the relationship Ke = CL/ Vd. As a result, the authors postulated that the uncorrected CrCl could possibly overor underestimate gentamicin maintenance doses for large and small patients, respectively, as their Vd would not be considered. To address this situation, Spyker and Guerrant proposed correcting CrCl to standard body size (mL/min per 70 kg or 1.73 m). This “corrected CrCl” would adjust for differences in Vd in patients of different sizes so that drug elimination could be correctly inferred from the nomogram. Sarubbi and Hull subsequently developed an amikacin dosage nomogram that incorporated corrected CrCl and reported slight but nonsignificant improvement in the correlation between predicted and observed concentrations relative to the uncorrected CrCl. A recent review states there is a lack of clarity around the optimal index of renal function for drug dosage adjustment. The weight containing CG equation (uncorrected) is often used by the pharmaceutical industry as a method for renal dosage adjustments. However, in 1988, D’Angio et al expressed concerns over using this version of the CG equation for renal drug dosage adjustment. Using hypothetical examples to illustrate pharmacokinetic concepts, D’Angio et al reminded readers that an uncorrected CrCl should not be used to compare elimination rates of renally cleared medications in patients of differing sizes because of differences in Vds. For such comparisons, D’Angio et al recommended a CrCl that is corrected to an average weight of 72 kg by multiplying the original CG formula by 72/body weight. This removes weight from the equation and simplifies the expression for males to (140 − Age)/SCr, which has units of mL/min/72 kg. Unfortunately, drug product information often does not specify whether CrCl should be corrected to 70 kg. In 1997, McCormack et al mentioned that standard dosage references often implicitly assume normal renal function is 100 to 120 mL/min/72 kg. McCormack et al added that empirical dosage adjustments should be based on a comparison between a weight corrected CrCl and a “normal” CrCl for a 72-kg man (100-120 mL/min). This allows for an apple-to-apple comparison of elimination rates (patient to standard reference) as the patient’s CrCl will be “corrected” to the size assumed by the reference. This permits comparison of elimination rates as both clearances are operating within identical Vds ensuring that both CL/Vd ratios are in proper proportion. In 2008, Dersch and McCromack reemphasized the concepts expressed by McCormack et al and added that the corrected CrCl is a relative CrCl and serves as a relative measure of renal function as it compares renal function from a specific individual with a reference point that defines “normal” renal function as 100 to 120 mL/min/72 kg. The functional range for creatinine clearance that has been proposed by Brown et al has intuitive appeal. However, this report did not address the pharmacokinetic concerns that have been raised by several authors over the past 30 years in regards to using weight in the CG equation. Therefore, it would seem prudent to exercise caution in using the original CG equation with weight if the intent is to compare renal function for the purpose of dosage modification. In addition, the functional creatinine clearance that is proposed by Brown et al requires knowledge of the patient’s weight and height (to determine ideal body 508746 AOPXXX10.1177/1060028013508746Ahern and PossidenteAnnals of Pharmacotherapy research-article2013