Regulatory perspectives on designing pharmacokinetic studies and optimizing labeling recommendations for patients with chronic kidney disease.
To optimize drug dosing, it is critical to understand how various intrinsic and extrinsic factors affect systemic exposure of the drug and the response. Chronic kidney disease (or renal impairment) can affect pharmacokinetic characteristics of a therapeutic drug and its metabolites and therefore is one of the most important intrinsic factors that can affect a patient's response to drugs. During drug development, it is critical to understand how renal impairment can affect a drug's pharmacokinetics so that appropriate dosing recommendations can be included in the label. The US Food and Drug Administration (FDA) has published various guidance documents and opinion papers to address scientific and regulatory issues in the study design, data analysis, and labeling recommendations related to dosing in patients with impaired renal function. The 2010 FDA draft guidance on renal impairment provides several updated recommendations that include criteria or principles for evaluating the pharmacokinetics of drugs that are either principally renally cleared or nonrenally cleared in subjects with renal impairment and for categorizing renal function by equations estimating glomerular filtration rate using the Modification of Diet in Renal Disease equations or creatinine clearance using the Cockcroft-Gault equation. The objective of this article is to discuss the FDA's current recommendations and provide examples that illustrate the importance of and challenges in studying effect of renal impairment during drug development.
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. leik.zhang@fda.hhs.gov
Lei
L
Zhang
Nancy
N
Xu
Shen
S
Xiao
Vikram
V
Arya
Ping
P
Zhao
Lawrence J
LJ
Lesko
Shiew-Mei
SM
Huang
D002908:Chronic Disease; D003404:Creatinine / Q000378:metabolism; D015195:Drug Design; D004341:Drug Evaluation / Q000592:standards*; D004348:Drug Labeling / Q000592:standards; D005919:Glomerular Filtration Rate; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D010599:Pharmacokinetics; D011506:Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D006435:Renal Dialysis; D012107:Research Design; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards
D011506:Proteins; D003404:Creatinine