Evaluation of novel biomarkers of nephrotoxicity in Cynomolgus monkeys treated with gentamicin

Journal Article · Fri Jul 15 00:00:00 EDT 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.04.012· OSTI ID:22689195

Gautier, Jean-Charles ^[1]; Zhou, Xiaobing ^[2]; Yang, Yi ^[3]; Gury, Thierry ^[1]; Qu, Zhe ^[2]; Palazzi, Xavier; Léonard, Jean-François; Slaoui, Mohamed; Veeranagouda, Yaligara; Guizon, Isabelle; Boitier, Eric; Filali-Ansary, Aziz ^[1]; Poetz, Oliver; Joos, Thomas ^[4]; Zhang, Tianyi ^[5]; Wang, Jufeng ^[2]; Detilleux, Philippe ^[1]; Li, Bo ^[2]

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1. Sanofi R&D, Vitry-sur-Seine (France)
2. National Center for Safety Evaluation of Drugs (NCSED), National Institutes for Food and Drug Control, Beijing (China)
3. Sanofi R&D, Bridgewater (United States)
4. Natural and Medical Sciences Institute at the University Tübingen (Germany)
5. Frontage Laboratories, Shanghai (China)

Most studies to evaluate kidney safety biomarkers have been performed in rats. This study was conducted in Cynomolgus monkeys in order to evaluate the potential usefulness of novel biomarkers of nephrotoxicity in this species. Groups of 3 males were given daily intramuscular injections of gentamicin, a nephrotoxic agent known to produce lesions in proximal tubules, at dose-levels of 10, 25, or 50 mg/kg/day for 10 days. Blood and 16-h urine samples were collected on Days − 7, − 3, 2, 4, 7, and at the end of the dosing period. Several novel kidney safety biomarkers were evaluated, with single- and multiplex immunoassays and in immunoprecipitation-LC/MS assays, in parallel to histopathology and conventional clinical pathology parameters. Treatment with gentamicin induced a dose-dependent increase in kidney tubular cell degeneration/necrosis, ranging from minimal to mild severity at 10 mg/kg/day, moderate at 25 mg/kg/day, and to severe at 50 mg/kg/day. The results showed that the novel urinary biomarkers, microalbumin, α1-microglobulin, clusterin, and osteopontin, together with the more traditional clinical pathology parameters, urinary total protein and N-acetyl-β-D-glucosaminidase (NAG), were more sensitive than blood urea nitrogen (BUN) and serum creatinine (sCr) to detect kidney injury in the monkeys given 10 mg/kg/day gentamicin for 10 days, a dose leading to an exposure which is slightly higher than the desired therapeutic exposure in clinics. Therefore, these urinary biomarkers represent non-invasive biomarkers of proximal tubule injury in Cynomolgus monkeys which may be potentially useful in humans. - Highlights: • Gentamicin induced kidney tubular cell degeneration/necrosis in Cynomolgus monkey • Urinary clusterin and osteopontin were sensitive biomarkers of kidney injury. • Microalbumin and α1-microglobulin in urine were also more sensitive than serum creatinine.

• OSTI ID: 22689195
• Journal Information: Toxicology and Applied Pharmacology, Vol. 303; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGICAL MARKERS
CREATININE
DRUGS
ENZYME IMMUNOASSAY
ENZYMES
INJURIES
INTRAMUSCULAR INJECTION
LIQUID COLUMN CHROMATOGRAPHY
MASS SPECTROSCOPY
MONKEYS
NECROSIS
NEUTROPHILS
RATS
TUBULES
UREA
URINE