INTRAVENOUS SINGLE AND REPEATED DOSE TOXICITY STUDIES OF CIMADRONATE (YM175), A NOVEL BISPHOSPHONATE, IN BEAGLE DOGS

Abstract

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 single and repeated dose toxicity studies of cimadronate in beagle dogs. In the single dose study, animals received a single dose of 0.3, 1, 3 or 10 mg/kg of cimadronate and the animals were observed for at least 14 days. At 10 mg/kg, both the male and female dog showed toxic signs such as vomiting, decreased locomotor activities and hypothermia and were killed in extremis within a week after dosing. In the 30-day study, animals received cimadronate at a dosage of 0 (vehicle), 0.03, 0.1, 0.3 or 1 mg/kg/day. At 0.03 mg/kg/day or more, histological findings indicated an increased amount of primary spongiosa in the rib and ilium. At 1 mg/kg/day, degenerative nephropathy, aggregation of spermatozoa and glandular hypoplasia of the prostate gland were observed. On day 16 of dosing one male animal died of acute renal failure. In the 26-week study, animals received cimadronate once weekly at a dosage of 0 (vehicle), 0.31, 0.62, or 1.25 mg/kg. Histopathological examination showed an increased amount of primary spongiosa in the rib at all dosage levels. In addition, similar findings were observed in the lumbar vertebrae at 1.25 mg/kg/week. Histopathological changes in the kidney and male reproductive organs were not observed.