Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate.
| Autor: | Powell CJ; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Kapeghian JC; Preclinical Safety Associates, LLC, The Woodlands, TX, USA., Bernal JC; CORES Veterinary Consulting, Walnut Grove, TX, USA., Foster JR; ToxPath Sciences Ltd, Congleton, UK. |
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| Jazyk: | angličtina |
| Zdroj: | International journal of toxicology [Int J Toxicol] 2024 Jul-Aug; Vol. 43 (4), pp. 368-376. Date of Electronic Publication: 2024 Mar 19. |
| DOI: | 10.1177/10915818241237992 |
| Abstrakt: | In a 3-month toxicity study in cynomolgus monkeys at a European contract laboratory, animals were infected with HAV, initially resulting in hepatic injury being incorrectly attributed to the test compound. Elevated serum ALT/AST/GLDH (5- to 10-fold) were noted in individual animals from all groups including controls, with no apparent dose, exposure, or time-related relationship. Liver histopathology revealed minimal to slight inflammatory cell accumulation in periportal zones of most animals, and minimal to slight hepatocyte degeneration/necrosis in 10/42 animals from all groups. As these findings were more pronounced in 6 drug-treated animals, including 2/6 in the low dose group, the draft report concluded: " treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL ." However, the unusual pattern of hepatotoxicity suggested a factor other than drug exposure might have caused the hepatic effects. Therefore, snap-frozen liver samples were tested for hepatitis viruses using a PCR method. Tests for hepatitis B, C, and E virus were negative; however, 20/42 samples were positive for hepatitis A virus (HAV). Infection was strongly associated with increased serum ALT/GLDH, and/or hepatocyte degeneration/necrosis. Re-evaluation of the study in light of these data concluded that the hepatic injury was not drug-related. A subsequent 6-month toxicology study in HAV-vaccinated cynomolgus monkeys confirmed the absence of hepatotoxicity. Identification of HAV infection supported progression of the drug candidate into later clinical trials. Although rarely investigated, subclinical HAV infection has occasionally been reported in laboratory primates, including those used for toxicology studies and it may be more prevalent than the literature indicates. Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors have acted as consultants for the sponsor of the studies. |
| Databáze: | MEDLINE |
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