Estimating Renal Function for Drug Dosing: Rewriting the Gospel? part 4
WHICH TESTAMENT SHOULD WE FOLLOW?
Various opinions on this topic have been expressed by pharmacy’s “disciples”, and one must carefully consider the underlying beliefs in an effort to get at the “truth”.
Belief 1: Because the MDRD equation is more accurate, it should be used for drug dosing.
Bailie and others were the first to state that pharmacists should switch to the MDRD equations because, according to data from the National Kidney Foundation, they were more accurate. However, the need for a more accurate test depends entirely on how the result will be used. Estimates of renal function, when used for dosage adjustments, are typically used in conjunction with drug dosing tables that have broad categories. For example, Drug Prescribing in Renal Failure and The Sanford Guide to Antimicrobial Therapy both use GFR categories of greater than 50, 10-50, and less than 10 mL/min for dosage recommendations. The product monograph for ciprofloxacin divides renal function into 2 categories (31-60 and less than 30 mL min-1 1.73 m-2) and provides maximum daily dosages for each. These categorizations have been set somewhat arbitrarily and are almost never based on a pharmacodynamic evaluation of the clinical impact of the dosing recommendations. Furthermore, they are also only loosely based on pharmacokinetic principles. When medications are marketed, the doses are rounded off to convenient amounts (e.g., 1000 mg instead of 875 mg) and intervals (q8h, not q9h or q5h). The use of tables and rounding of doses and intervals produces far greater variation in the dose received than almost any differences that would be caused by different estimates of renal function.
Belief 2: The MDRD equations should not be used because the manufacturers’ recommended dosage adjustments are based on the CG equation; using a different formula than the one traditionally used by manufacturers will lead to errors in dosage adjustments.
In a commentary in Pharmacotherapy, Bauer stated that pharmacists should not switch to GFR estimation equations (such as the MDRD equations), noting that most pharmacokinetic studies done to create renal dosing recommendations have used estimates of creatinine clearance, not GFR, as per guidelines from the US Food and Drug Administration. In July 2006, the National Kidney Disease Education Program issued a statement recommending that pharmacists continue to use current dosing practices (i.e., with the CG equation) because the impact on drug dosage adjustment with the MDRD equation had not yet been examined. In a recent article, Spruill and others provided a comprehensive review of the use of the MDRD equations for drug dosing, concluding that pharmacists should continue to use the CG equation, as this formula had provided the framework for drug dosing research and recommendations.
In a systematic review, Vidal and others examined 4 drug information sources and found “remarkable variation in definitions and recommendations”. They concluded that available resources were “ill suited for clinical use”. The editors of the drug information sources responded that, because of a lack of regulatory requirements for renal dosing studies and the myriad clinical factors involved,26 drug prescribing in renal failure “remains imprecise,” relying on “interpolation, extrapolation, and estimation”. In particular, the editor of Drug Prescribing in Renal Failure stated that dosing for older drugs is based on “flimsy data, such as case reports, common practice, and pharmacokinetic extrapolation from patients with normal renal function”. In addition to these points, pharmacists must be mindful that most recommendations for dosage adjustment have never been evaluated pharmacody- namically to determine if the adjusted doses produce the same benefit and carry similar potential for harm.
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Belief 3: The MDRD equation should not be used because it has not been validated for drug dosing purposes.
Wolowich and others have pointed out that the MDRD equation has never been validated for the purposes of drug dosing and so would be an inappropriate replacement for the CG equation. While this is technically correct, to our knowledge the same is true for the CG equation. The fact that it was the first equation used for this purpose does not make it the “correct” equation.
Belief 4: The MDRD equation should not be used because it reports relative renal function (units of mL min-1 1.73 m-2) rather than actual renal function (units of mL/min).
Wolowich and others3 also argued that if the MDRD equation is used, “dosing errors will occur” because of the units (mL min-1 1.73 m-2, rather than mL/min). These authors state that drug dosage recommendations should use individualized GFR estimates (mL/min, not mL min-1 1.73 m-2), and the MDRD results must therefore be multiplied by the patient’s body surface area to achieve the correct value. However, as discussed above (see the section entitled “Blasphemy”), using relative renal function estimates is probably the more pharmacokineti- cally correct way to adjust dosing intervals.
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