Investigation of Correlation between safety biomarkers in serum, histopathological examination and toxicogenomics
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Wang, Tao, Papoutsi, Maria, Decristofaro, Marc, Keselica, Michael, Skuba, Elizabeth, Spaet, Robert, Markovits, Judit, Wolf, Armin, Moulin, Pierre, Pognan, Francois, Vancutsem, Paul, Petryk, Lew and Kluwe, William (2011) Investigation of Correlation between safety biomarkers in serum, histopathological examination and toxicogenomics. International Journal of Toxicology. ISSN 1091-5818
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
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | ALT elevation, toxicogenomics, histopathology |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/3741 |