Drug Dosing and Estimated Renal Function - Any Step Forward from Effersoe?

Abstract

Drug dosing in accordance with the renal function is a long-standing challenge to clinicians. For many years it has been evident that in many clinical situations there is no easy way to correctly dose any drug that is mainly cleared by the kidneys. Despite the development of many formulas for estimating the glomerular filtration rate, they all have serious shortcomings. Much effort has been put in to develop estimation formulas to evaluate the renal function as an alternative to direct methods with the aim of safely dosing drugs that are mainly cleared by the kidneys. Both creatinine- and cystatin C-based formulas with additional clinical and biochemical parameters deduced from association studies with methods to measure the glomerular filtration rate (mGFR) have been developed. None of them have been good enough to perform safely in the wide range of situations in daily clinical praxis. Despite serious limitations, there has also been a tendency to use estimated GFR (eGFR) as a “hard” clinical endpoint in clinical studies. This has increased the risk of misinterpretation and has led to conclusions that are not necessarily supported by data. Finally, new methods of testing drug toxicity and the use of pharmacological support in order to fix the right doses are mentioned in this short overview of studies; possible problems that are encountered using eGFR instead of mGFR in the clinic and in research are also mentioned in this report.

Kidney function estimates using cystatin C versus creatinine: Impact on medication prescribing in acutely hospitalized elderly patients

“…The Kidney Disease Improving Global Outcome (KDIGO) and Danish Society of Nephrology both recommend CKD‐EPI Cr for the diagnosis and treatment of kidney disease, and it is commonly used for medication prescribing in the clinic . However, creatinine is heavily dependent on age, sex, muscle mass and nutritional status, and CKD‐EPI Cr is known to overestimate GFR in acutely hospitalized elderly patients …”

Reply to ‘Strengths and limitations of estimated and measured GFR’

“…1). Indeed, there is evidence that this level of error in eGFR has important consequences including overdosing or underdosing of toxic drugs 15 , erroneous classification of chronic kidney disease (CKD) stages 10 , accepting kidney donors with low GFR and rejecting potential donors with…”

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

“…However, methods used to measure renal function through the glomerular filtration rate (GFR) or surrogates thereof are time intensive and impractical in most clinical settings. 3 Thus, drug dosing is largely determined using estimates of GFR obtained from equations based on demographic variables and 1 or more renal biomarkers. 3 The Cockcroft-Gault (C-G) estimate of creatinine clearance (eCrCL) has been the standard used to enroll patients with renal impairment into phase 1 PK studies, inform dosing protocols in late-phase clinical trials, and stratify dosing schedules in product labeling.…”

“…3 Thus, drug dosing is largely determined using estimates of GFR obtained from equations based on demographic variables and 1 or more renal biomarkers. 3 The Cockcroft-Gault (C-G) estimate of creatinine clearance (eCrCL) has been the standard used to enroll patients with renal impairment into phase 1 PK studies, inform dosing protocols in late-phase clinical trials, and stratify dosing schedules in product labeling. 4 However, since publication of draft guidance from the United States Food and Drug Administration (FDA) in 2010, this paradigm has been shifting toward the Modification of Diet in Renal Disease (MDRD) estimate of glomerular filtration rate (eGFR), despite the lack of a clear recommendation in favor of this equation over the C-G. 5,6 Conversely, the European Medicines Agency (EMA) recommends an exogenous measure of GFR be used in these early-phase clinical trials.…”