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Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/ kg/ day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/ kg/ day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively). Rosiglitazone was not carcinogenic in the mouse. Text Continues Below
There was an increase in incidence of adipose hyperplasia in the mouse at doses 1.5 mg/ kg/ day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses 0.3 mg/ kg/ day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue. Mutagenesis: Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/ in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation. Impairment of Fertility: Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/ kg/ day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/ kg/ day) and reduced fertility (40 mg/ kg/ day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/ kg/ day (approximately 3 times human AUC at the maximum recommended human daily dose). Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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