title: Investigation of correlation among safety biomarkers in serum, histopathological examination, and toxicogenomics.
abstract: This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations.
authors.affiliation: Translational Sciences, Novartis Institute of Biomedical Research, Emeryville, CA, USA. tao.wang@novartis.com
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Papoutsi
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: Marc
authors.initials: M
authors.lastname: DeCristofaro
authors.forename: M Craig
authors.initials: MC
authors.lastname: Keselica
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Skuba
authors.forename: Robert
authors.initials: R
authors.lastname: Spaet
authors.forename: Judit
authors.initials: J
authors.lastname: Markovits
authors.forename: Armin
authors.initials: A
authors.lastname: Wolf
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.forename: Francois
authors.initials: F
authors.lastname: Pognan
authors.forename: Paul
authors.initials: P
authors.lastname: Vancutsem
authors.forename: Lew
authors.initials: L
authors.lastname: Petryk
authors.forename: James
authors.initials: J
authors.lastname: Sutton
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.forename: William
authors.initials: W
authors.lastname: Kluwe
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000235:genetics; D052160:Benzothiazoles / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood*; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008252:Macaca fascicularis; D010597:Pharmacogenetics; D010848:Picolinic Acids / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018675:Toxicity Tests; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C568289:4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide; D052160:Benzothiazoles; D015415:Biomarkers; D010848:Picolinic Acids; D012333:RNA, Messenger; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase