General toxicity study of gadobenate dimeglumine formulation (E7155) (4)--4-week repeated dose intravenous toxicity study followed by 4-week recovery period in dogs

Abstract

Gadobenate dimeglumine formulation (E7155), at doses of 0 (physiological saline), 0.25, 0.5, 1 and 2 mmol/kg/day of body weight, was administered intravenously to male and female beagle dogs once daily for 4 consecutive weeks in order to evaluate the subacute toxicity of the test article. Reversibility of toxicity was evaluated during a 4-week recovery period at 1 and 2 mmol/kg/day. No toxicologically significant changes were observed at 0.25 and 0.5 mmol/kg/day. In animals receiving 1 or 2 mmol/kg/day, transient swelling and redness of the facial and eye areas, lethargy, decreased activity, emesis, retching, watery or unformed stool, decreased body weight or body weight gain, decreased food consumption, decreased hematocrit and hemoglobin concentration, increased APTT, increases in plasma ALP, GPT or gamma-GT, decreased plasma inorganic phosphorus, total protein or albumin, increased liver or kidney weight, subacute inflammatory infiltrates, loss of centrilobular hepatocytes or hepatocellular cytoplamic vacuolation in the liver, vacuoles in the epithelial cells of the renal tubles and/or hypocellularity in the bone marrow were seen. The results of toxicokinetic analysis showed that systemic exposure was similar in males and females, and there was no accumulation of the test material over the treatment period, although AUC tended to be enhanced by slightly more than the proportionate dose increase. These effects were recovered or tended to be reversed after a post-dosing period for 4 weeks. In conclusion, the No Observed Adverse Effect Level (NOAEL) was 0.5 mmol/kg/day.