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 The 2010 FDA draft guidance on renal impairment provides several updated recommendations that include criteria or principles for evaluating the pharmacokinetics of drugs that are either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.