Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits.
Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous reproductive toxicity and teratology studies (Segment I, II and III) of this compound in rats and teratology study in rabbits. The test compound was dissolved in physiological saline, which was also given as the vehicle control. Rats were administered at a dosage of 0.06, 0.16 and 0.62 mg/kg/day in the male Segment I study. Dose levels in the other studies in rats including the female Segment I were 0.16, 0.31 and 0.62 mg/kg/day. In the Segment I study, no treatment-related abnormalities were observed in reproductive parameters or fetuses. In the Segment II study, slightly retarded fetal ossification was noted at 0.31 mg/kg/day or more, but the incidence of malformation did not increase. In the Segment III study, death of the dams and abnormal tooth growth of offspring were observed at 0.16 mg/kg/day or more. Further Segment III study showed that the no toxic effect level was 0.003 mg/kg/day. In the rabbit teratology study, dose levels were 0.01, 0.025 or 0.05 mg/kg/day. No toxic effects on pregnant females or their litters were observed at up to 0.05 mg/kg/day.
D000014:Abnormalities, Drug-Induced; D000818:Animals; D004164:Diphosphonates / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility / Q000187:drug effects; D005333:Fetus / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D004164:Diphosphonates; C071542:cimadronate