Studies in rodents with the dipeptidyl peptidase‐4 inhibitor vildagliptin to evaluate possible drug‐induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man. Issue 1 (9th September 2012) - Busch, S. J.
Abstract Aim The present report summarizes rodent studies with vildagliptin, relevant to predicting pancreatitis or pancreatic cancer in man. 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and rat) carcinogenicity studies that were conducted according to guidelines assigned in Food and Drug Administration's Draft Guidance for Industry.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 1000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). The results from these studies show the expected preservation and growth of the endocrine β‐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 2‐year preclinical carcinogenicity studies in both rats and mice indicates 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.