Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor.
Drug-induced kidney injury (DIKI) results in attrition during drug development; new DIKI urinary biomarkers offer potential to detect and monitor DIKI progression and regression, but frequently only in rats. The triple reuptake inhibitor (TRI) PRC200-SS represents a new class of antidepressants that elevate synaptic levels of serotonin, norepinephrine, and dopamine and is expected to produce more rapid onset and better antidepressant efficacy than single or dual inhibitors. Although preclinical studies and recent clinical trials lend support to this concept of superior efficacy for TRIs, there is little information on the safety profile of this class of compounds. Using histopathology and DIKI biomarkers, in single- and repeat dose toxicological studies in cynomolgus monkeys, PRC200-SS demonstrated dose-proportional kidney toxicity. Characterization of the histopathological lesions, using a combination of immunohistochemistry (IHC) and urinary biomarker analysis, indicated that the compound is a distal tubule and collecting duct toxicant. Segment specificity for the lesions was shown using a newly developed triple IHC combination method with antibodies against calbindin D28, aquaporin 2, and aquaporin 1. Urinary biomarker analyses, using multiplex immunoassays, confirmed a dose-proportional increase in the excretion of calbindin D28 and clusterin in compound-treated monkeys with levels returning to baseline during the drug-free recovery period. These results constitute the validation of distal nephron DIKI biomarkers in the cynomolgus monkey and demonstrate the utility of calbindin D28 and clusterin to monitor the progression of distal nephron DIKI, representing potential early biomarkers of DIKI for the clinic.
AstraZeneca, Safety Assessment, Wilmington, Delaware 19850, USA.
Mausumee
M
Guha
Annabelle
A
Heier
Sally
S
Price
Margareta
M
Bielenstein
Robert G
RG
Caccese
Daniel I
DI
Heathcote
Thomas R
TR
Simpson
David B
DB
Stong
Elmarie
E
Bodes
D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001711:Biotransformation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D008252:Macaca fascicularis; D008297:Male; D009281:Naphthalenes / Q000493:pharmacokinetics / Q000633:toxicity*; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010865:Pilot Projects; D011412:Propanolamines / Q000493:pharmacokinetics / Q000633:toxicity*
C532889:3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol; D000928:Antidepressive Agents; D015415:Biomarkers; D009281:Naphthalenes; D014179:Neurotransmitter Uptake Inhibitors; D011412:Propanolamines