Evaluation of novel biomarkers of nephrotoxicity in Cynomolgus monkeys treated with gentamicin.
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 50mg/kg/day for 10days. 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 10mg/kg/day, moderate at 25mg/kg/day, and to severe at 50mg/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 10mg/kg/day gentamicin for 10days, 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.
Sanofi R&D, Vitry-sur-Seine, France. Electronic address: jean-charles.gautier@sanofi.com.
Jean-Charles
JC
Gautier
National Center for Safety Evaluation of Drugs (NCSED), National Institutes for Food and Drug Control, Beijing, China.
Xiaobing
X
Zhou
Sanofi R&D, Bridgewater, USA.
Yi
Y
Yang
Sanofi R&D, Vitry-sur-Seine, France.
Thierry
T
Gury
National Center for Safety Evaluation of Drugs (NCSED), National Institutes for Food and Drug Control, Beijing, China.
Zhe
Z
Qu
Sanofi R&D, Vitry-sur-Seine, France.
Xavier
X
Palazzi
Sanofi R&D, Vitry-sur-Seine, France.
Jean-François
JF
Léonard
Sanofi R&D, Vitry-sur-Seine, France.
Mohamed
M
Slaoui
Sanofi R&D, Vitry-sur-Seine, France.
Yaligara
Y
Veeranagouda
Sanofi R&D, Vitry-sur-Seine, France.
Isabelle
I
Guizon
Sanofi R&D, Vitry-sur-Seine, France.
Eric
E
Boitier
Sanofi R&D, Vitry-sur-Seine, France.
Aziz
A
Filali-Ansary
Natural and Medical Sciences Institute at the University Tübingen, Germany.
Bart H J
BHJ
van den Berg
Natural and Medical Sciences Institute at the University Tübingen, Germany.
Oliver
O
Poetz
Natural and Medical Sciences Institute at the University Tübingen, Germany.
Thomas
T
Joos
Frontage Laboratories, Shanghai, China.
Tianyi
T
Zhang
National Center for Safety Evaluation of Drugs (NCSED), National Institutes for Food and Drug Control, Beijing, China.
Jufeng
J
Wang
Sanofi R&D, Vitry-sur-Seine, France.
Philippe
P
Detilleux
National Center for Safety Evaluation of Drugs (NCSED), National Institutes for Food and Drug Control, Beijing, China. Electronic address: libo@nifdc.org.cn.
Bo
B
Li
D000118:Acetylglucosaminidase / Q000652:urine; D000410:Alanine Transaminase / Q000097:blood; D000510:Alpha-Globulins / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D051152:Clusterin / Q000652:urine; D003401:Creatine / Q000097:blood / Q000652:urine; D005839:Gentamicins / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine*; D008252:Macaca fascicularis; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D053495:Osteopontin / Q000652:urine; D012709:Serum Albumin / Q000032:analysis
D000510:Alpha-Globulins; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D001786:Blood Glucose; D051152:Clusterin; D005839:Gentamicins; D012709:Serum Albumin; C016001:alpha-1-microglobulin; D053495:Osteopontin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000118:Acetylglucosaminidase; D003401:Creatine
Cynomolgus monkeys; Gentamicin; Kidney; Safety biomarkers; Singleplex and multiplex assays