title: A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models.
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.
authors.affiliation: The Hamner Institutes for Health Sciences, Hamner-University of North Carolina Institute for Drug Safety Sciences, Durham, North Carolina 27709, USA. aharrill@thehamner.org
authors.forename: Alison H
authors.initials: AH
authors.lastname: Harrill
authors.forename: Kristina D
authors.initials: KD
authors.lastname: Desmet
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Wolf
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: J Scott
authors.initials: JS
authors.lastname: Eaddy
authors.forename: C Lisa
authors.initials: CL
authors.lastname: Kurtz
authors.forename: J Ed
authors.initials: JE
authors.lastname: Hall
authors.forename: Mary F
authors.initials: MF
authors.lastname: Paine
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001550:Benzamidines / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001806:Blood Urea Nitrogen; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003404:Creatinine / Q000097:blood; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D000072596:Hepatitis A Virus Cellular Receptor 1; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000652:urine; D008297:Male; D008565:Membrane Proteins / Q000652:urine; D051379:Mice; D018570:Risk Assessment; D013045:Species Specificity; D018675:Toxicity Tests / Q000379:methods; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D001550:Benzamidines; D015415:Biomarkers; D005819:Genetic Markers; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D014344:Trypanocidal Agents; D003404:Creatinine; C458513:pafuramidine