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Endocrinology. 2015 Jul;156(7):2417-28. doi: 10.1210/en.2014-1722. Epub 2015 Apr 10.

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents.

Author information

1
Department of Toxicology, Pathology, and Drug Disposition (R.A.B., J.A.W., H.W.S., J.L.B., J.A.M., J.L.V.), Eli Lilly and Company, Indianapolis, Indiana 46285; Early Development (S.D.S., T.R., T.P., R.L., R.Q.), Covance Laboratories, Madison, Wisconsin 53704; Department of Veterinary Biosciences (T.J.R.), The Ohio State University, Columbus, Ohio 43210; and Experimental Pathology Laboratories, Inc (G.G.L.), Sterling, Virginia 20166.

Abstract

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.

PMID:
25860029
DOI:
10.1210/en.2014-1722
[Indexed for MEDLINE]

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