Drug dosing and new measures of serum creatinine: Clear as mud

Appropriate drug dosing requires an estimation of kidney function that is reliable and consistent across many clinical scenarios and laboratory settings. Historically, many methods have been utilized to estimate renal function, all of which have advantages and disadvantages.

In 2006, the National Kidney Disease Education Program (NKDEP) Laboratory Working Group, in collaboration with the International Federation of Clinical Chemistry and Laboratory Medicine, and the European Communities Confederations of Clinical Chemistry, published standardized methods for measuring serum creatinine levels. These recommendations were expected to be implemented internationally by early 2010; therefore, some laboratories are just now coming into compliance.

These recommendations stemmed from National Kidney Foundation guidelines, which recommended based on the Modification of Diet in Renal Disease (MDRD) study the reporting of an estimated glomerular filtration rate (GFR) as the standard screening method for chronic renal disease.

This equation was originally validated utilizing a non-isotope dilution mass spectrometry (IDMS) creatinine value, but validation studies indicated the creatinine component of this equation was highly variable. Therefore, the NKDEP Laboratory Working Group was developed to establish a calibration methodology to standardize creatinine measurements across laboratories.

Laura Boehnke Michaud

The new standard IDMS creatinine measurement is reliable and accounts for variations between laboratories. When utilized in the revised MDRD (4-variable) equation, the IDMS creatinine value allows increased predictability in identifying patients with chronic renal disease and may potentially improve outcomes for patients at risk for this disease (see sidebar). Because these formulas were developed for screening and diagnosis of chronic renal disease, their validity in drug dosing has been controversial and the subject of many reviews. As is shown in Table 1 (see page 14), the IDMS creatinine value is approximately 5% to 20% lower than the non-IDMS creatinine value (using one available conversion factor).

Measuring creatinine clearance

Historically, the gold standard for estimating creatinine clearance as it relates to drugs is the Cockcroft-Gault equation (see sidebar). This equation takes into account the age, weight, sex and serum creatinine value of the patient to estimate creatinine clearance (Cl_CR) in milliliters per minute. This equation was first validated in a small cohort of patients in the 1970s and originally used total body weight and a non-IDMS serum creatinine level.

The limitations of this formula for estimating renal clearance of drugs have been well documented. Extremes of weight (obese or cachectic), age (old or young), race, and/or renal function (as reflected in serum creatinine value) are associated with a much weaker correlation between the patient’s actual renal function and their estimated Cl_CR utilizing the Cockcroft-Gault formula compared with the gold standard for measuring Cl_CR (radiolabeled, 24-hour urine creatinine analysis). Therefore, over the years, clinicians have compensated for these shortcomings by carefully choosing the values in the formula to more accurately reflect the individual clinical scenario. The resulting value from the Cockroft-Gault equation was not normalized for body surface area, as are many other formulas (eg, MDRD), but the adjusted body weight incorporated into the equation is able to account for differences in body size (eg, ideal body weight or adjusted body weight).

For patients with low serum creatinine levels (<0.5 mg/dL) who are elderly or frail (low muscle mass), clinicians should consider using an empiric serum creatinine of 0.8 mg/dL or 1 mg/dL in the Cockcroft-Gault equation to accommodate for these low values. Secondarily, for patients who are obese or cachectic (extremes of weight), clinicians should consider using an adjusted or ideal body weight instead of actual body weight for estimating Cl _CR or normalizing the value for body surface area (although the latter is not generally recommended). Another method to accommodate for extremes in weight would be to cap the Cl_CR value at approximately 120 mL/min, which would be considered the maximum renal clearance for an adult.

Overall, these decisions should also take into account the general health of the patient, goals of therapy and other clinical factors that may determine drug therapy tolerability. For example, a clinician may want to be more aggressive with dosing a chemotherapy agent in a young, curable patient compared with an elderly, frail patient with metastatic disease and multiple comorbidities. These decisions are complex and require a great deal of thought and a clear understanding of the limitations of our estimates.

Chemotherapy dose adjustments

For cancer chemotherapy and biotherapy, there are a handful of agents that rely on the kidney for elimination and require dose adjustment for renal dysfunction (see Table 2). All of these agents have a relatively narrow therapeutic range, and proper dose selection is important for minimizing risks and optimizing tumor outcomes (eg, increased response rates and survival).

Of these agents, carboplatin is perhaps the most cumbersome and complex in its dosing recommendations. Based on clinical trials conducted in the 1990s, the preferred dosing method for carboplatin is not based on body surface area. Instead, the dosing formula, first published by Calvert and colleagues, is often used for carboplatin, whether administered as a single agent or in combination (see sidebar on page 4).

This formula multiplies the target area under the concentration vs. time curve (AUC) with GFR + 25 (which represents the proportion of non-renal clearance for carboplatin) and uses this total dose value as the individualized dose for a single patient. This method of calculating total dose was first validated using a measured Cl_CR through a radiolabeled, 24-hour urine collection assay. Nonetheless, incorporation of estimated Cl_CR values (from the Cockcroft-Gault equation) into the Calvert equation has become the standard of care for most patient populations, with the exception of perhaps pediatrics and stem cell transplant patients, in which the risks of toxicity are high and the more accurate methodology is preferred.

Most clinical trials that incorporated an estimated Cl_CR into the Calvert formula for carboplatin did so using a non-IDMS creatinine value as well. Therefore, this equation has become a “rough” estimate of actual renal clearance and drug dosing. Caution should be used when choosing values to plug into these formulas, as each individual component can profoundly change the total dose calculation and potentially lead to increased risk of toxicity (see Table 1). Individualization of the formulas used for each clinical situation is paramount to optimizing the use of carboplatin in all patient populations.

Making an informed decision

For many drugs, renal dosing recommendations are based on non-IDMS creatinine values. It is unreasonable to think that revalidation of drug dosing guidelines will occur for all agents currently on the market. It also seems unrealistic to think that clinicians should forever back-calculate to a non-IDMS serum creatinine for drug dosing. After all, these are just estimates of renal function. The FDA may require that certain drugs undergo further validation using standardized methods for measuring creatinine; however, this has yet to be determined.

For patients being treated with renally cleared chemotherapy (or other drugs), the most prudent course of action appears to be to use the reported IDMS creatinine value, recognizing that the non-IDMS value would be about 5% to 20% higher.

Taking this into account will allow the utilization of published dosing guidelines along with other clinical information to make an informed decision for an individual patient. For patients being treated as part of a clinical trial, the research protocol should clearly state how to calculate drug doses and how to handle IDMS and non-IDMS creatinine values to ensure consistency in dosing throughout the life of the study, especially with carboplatin dosing.

The bottom line on this subject is that all clinicians should be aware of what method their laboratory uses to measure serum creatinine. A second caveat is to be aware of and understand drug dosing in patients with renal dysfunction and the limitations of formulas and equations for choosing a dose or estimating renal function.

A better approach moving into the future seems to be to focus on other dosing parameters that may be more objective and individualized, such as identifying genetic variations that may predispose patients to risks or benefits from drug therapy.

Although there is likely not an easy, one-size-fits-all approach that will suffice for optimizing drug therapy in cancer patients, continued research and dedication to exploring these clinical questions will help to further understand and predict how patients will respond to therapy.

Laura Boehnke Michaud, PharmD, BCOP, FASHP, is manager of Clinical Pharmacy Services at The University of Texas M.D. Anderson Cancer Center, Houston.

For more information:

• Calvert AH. J Clin Oncol. 1989;7:1748-1756.
• Chronic kidney disease and drug dosing: information for providers. Accessed June 21, 2010 at: www.nkdep.nih.gov/professionals/CKD_DrugDosing_508.pdf.
• Cockroft DW. Nephron. 1976;16:31-41.
• Gault MH. Nephron. 1992;62:249-256.
• Myers GL. Clin Chem. 2006;52:5-18.
• Spruill WJ. Am J Health-Syst Pharm. 2007;64:652-660.
• Spruill WJ. Clin Pharmacol Ther. 2009;86:468-470.
• US Food and Drug Administration. Preliminary concept paper: Pharmacokinetics in patients with impaired renal function – study design, data analysis, and impact on dosing and labeling. Presented at: the FDA Clinical Pharmacology Advisory Committee Meeting; March 19, 2008; Rockville, Md. Accessed at: www.regulations.gov/search/Regs/home.html#documentDetail?R=09000064803acc8f.
• Wade WE. Ann Pharmacother. 2007;41:475-480.