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CC BY-NC V4.0, Open Access
Journal article
A Mouse Diversity Panel Approach Reveals the Potential for Clinical Kidney Injury Due to DB289 Not Predicted by Classical Rodent Models
Toxicological sciences, Vol.130(2), pp.416-426
12/2012
Handle:
https://hdl.handle.net/2376/113609
PMCID: PMC3498743
PMID: 22940726
Abstract
DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next-in-class compounds for renal injury.
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Details
- Title
- A Mouse Diversity Panel Approach Reveals the Potential for Clinical Kidney Injury Due to DB289 Not Predicted by Classical Rodent Models
- Creators
- Alison H Harrill - *Kristina D DeSmet - *Kristina K Wolf - †Arlene S Bridges - ‡J. Scott Eaddy - *C. Lisa Kurtz - *J. Ed Hall - ‡Mary F Paine - †Richard R Tidwell - ‡Paul B Watkins - *
- Publication Details
- Toxicological sciences, Vol.130(2), pp.416-426
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- Oxford University Press; US
- Number of pages
- 11
- Identifiers
- 99900547455901842
- Language
- English
- Resource Type
- Journal article