Rationale and objectives: A series of preclinical tests were undertaken during the developmental process to determine the safety profile of gadoversetamide injection (OptiMARK).
Methods: Acute intravenous, acute intracisternal, and repeated-dose toxicities; cardiovascular effects; and genetic and reproductive toxicology characteristics were assessed in several animal species.
Results: Gadoversetamide injection demonstrated an acute intravenous median lethal dose of 25 to 28 mmol/kg and a maximum nonlethal dose of 14 mmol/kg in mice. In the dog, acute administration of gadoversetamide injection showed a no observable effect level at 3 mmol/kg. Dosed daily for 4 weeks, gadoversetamide injection (0.1 mmol x kg(-1) x d(-1)) caused no serious irreversible changes in any organs in rats and dogs. At a dose of 0.1 mmol/kg, gadoversetamide injection caused no significant (P < 0.05) changes in cardiovascular function in anesthetized dogs. Gadoversetamide injection showed no mutagenic activity. Fertility, reproductive performance, and postnatal fetal development were not affected at doses up to 0.5 mmol x kg(-1) x d(-1) in the rat. No teratogenicity was observed at doses up to 4.2 mmol x kg(-1) x d(-1) in the rat and up to 1.6 mmol x kg(-1) x d(-1) in the rabbit.
Conclusions: Data from our toxicological assessment demonstrate the safety of gadoversetamide injection in a number of animal species at doses exceeding the intended human clinical dose.