Studies in rodents with the DPP-4 inhibitor vildagliptin to evaluate possible drug-induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man.
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Busch, Steven, Hoffmann, Peter, Foley, James, Sahota, Pritam, Johnson, Robert, Kothny, Wolfgang and Meyer, Franck (2012) Studies in rodents with the DPP-4 inhibitor vildagliptin to evaluate possible drug-induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man. Diabetes, Obesity and Metabolism.
Abstract
Aim: The present report summarizes rodent studies with vildagliptin, relevant to
predicting pancreatitis or pancreatic cancer in man.
Research design and Methods: As part of the regulatory development program for
vildagliptin, a rodent toxicity program included two 104 week rodent (mouse and rat)
carcinogenicity studies that were conducted according to guidelines assigned in FDA’s
Draft Guidance for Industry.
Results: Vildagliptin exposure in animals was evaluated for its effects on endocrine and
exocrine pancreas. Two-year carcinogenicity studies were conducted in rats at oral doses
up to 900 mg/kg (approximately 200 times the human exposure at the maximum
recommended dose) and in mice at oral doses up to 1,000 mg/kg (up to 240 times the
human exposure at the maximum recommended dose). The results from these studies
demonstrate the expected preservation and growth of the endocrine beta cells with no
significant findings in the exocrine acinar pancreas. There was no evidence of
inflammatory infiltrates characteristic of pancreatitis, no palpable mass detection based
on gross examination or any microscopic findings indicative of pancreatic islet cell
(endocrine), acinar cell (exocrine) or ductal (exocrine) neoplasia in rat or mouse.
Conclusions: Evaluation of vildagliptin in two-year preclinical carcinogenicity studies in
both rats and mice indicate that while vildagliptin results in pharmacological benefits to
the endocrine pancreas, this was not associated with any evidence of pancreatitis,
pancreatic islet cell, acinar cell or ductal neoplasia. These data predict no increased risk
of pancreatic cancer in man.
Keywords: adverse effects, dipepti
| Item Type: | Article |
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| Related URLs: | |
| Keywords: | T2DM, diabetes, pancreatitis, preclinical, DPP-4, GLP-1, drug safety |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6252 |