13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily oral doses of zoledronic acid of 0.1, 0.5, or 2 mg/kg/day for 2 years. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (starting at doses equivalent to 0.002 times the human 5 mg intravenous dose, based on body surface area, mg/m2). Rats were given daily oral doses of zoledronic acid of 0.1, 0.5, or 2 mg/kg/day for 2 years. No increased incidence of tumors was observed at any dose (up to 0.1 times the human intravenous dose of 5 mg, based on body surface area, mg/m2).
Mutagenesis: Zoledronic acid was not genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese hamster gene mutation assay, with or without metabolic activation. Zoledronic acid was not genotoxic in the in vivo rat micronucleus assay.
Impairment of Fertility: Female rats were given daily subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg beginning 15 days before mating and continuing through gestation. Inhibition of ovulation and a decrease in the number of pregnant rats were observed at 0.1 mg/kg/day (equivalent to the human 5 mg intravenous dose, based on AUC). An increase in preimplantation loss and a decrease in the number of implantations and live fetuses were observed at 0.03 and 1 mg/kg/day (0.3 to 1 times the human 5 mg human intravenous dose).
13.2 Animal Pharmacology
Bone Safety Studies: Zoledronic acid is a potent inhibitor of osteoclastic bone resorption. In the ovariectomized rat, single IV doses of zoledronic acid of 4 to 500 mcg/kg (0.1 to 3.5 times the human 5 mg intravenous dose, based on body surface area, mg/m2) suppressed bone turnover and protected against trabecular bone loss, cortical thinning and the reduction in vertebral and femoral bone strength in a dose-dependent manner. At a dose equivalent to human exposure at the 5 mg intravenous dose, the effect persisted for 8 months, which corresponds to approximately 8 remodeling cycles or 3 years in humans.
In ovariectomized rats and monkeys, weekly treatment with zoledronic acid dose-dependently suppressed bone turnover and prevented the decrease in cancellous and cortical BMD and bone strength, at yearly cumulative doses up to 3.5 times the human 5 mg intravenous dose, based on body surface area, mg/m2. Bone tissue was normal and there was no evidence of a mineralization defect, no accumulation of osteoid, and no woven bone.