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Semin Nephrol. 2019 Mar;39(2):120-131. doi: 10.1016/j.semnephrol.2018.12.002.

Kidney Safety Assessment: Current Practices in Drug Development.

Author information

1
Merck Research Laboratories, Department of Safety Assessment and Laboratory Animal Resources, West Point, PA. Electronic address: sean_troth@merck.com.
2
Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, NJ.
3
Pfizer, Inc, Clinical Development and Operations, Inflammation and Immunology, Collegeville, PA.
4
Pfizer Global Research and Development, Drug Safety Research and Development, Groton, CT.
5
Merck Research Laboratories, Department of Safety Assessment and Laboratory Animal Resources, West Point, PA.

Abstract

The kidney's role as a major route of metabolism and clearance of xenobiotics and its ability to concentrate the glomerular filtrate make it particularly vulnerable to drug-induced toxicity. Improving kidney safety is an active area of research and there is a need in early stages of drug development for strategies and model systems to reliably identify nephrotoxic compounds and sufficiently characterize mechanisms to support drug pipeline decision making. In later stages of drug development the value of sensitive translational biomarkers to monitor kidney toxicity across species in nonclinical and clinical settings is gaining realization. Various tools and strategies for kidney safety assessment have emerged over the past decade; however, there is currently no clear consensus on best practices for their use across different phases of drug development. Here, we provide perspective on the scope of this problem in drug development, and an overview of progress in the field of kidney safety including several informative case examples of kidney toxicity de-risking scenarios encountered in the pharmaceutical industry. The results of a survey of pharmaceutical companies conducted through the Innovation and Quality Drug Safety consortium provides additional insight into recent experiences with compound attrition and different de-risking approaches across the industry.

KEYWORDS:

Nephrotoxicity; biomarkers; drug attrition; drug safety; kidney; prediction

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