Toxicological assessment of gadoversetamide injection (OptiMARK), a new contrast-enhancement agent for use in magnetic resonance imaging.
OBJECTIVE
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.
Wible
J H
JH
Mallinckrodt Imaging, St. Louis, Missouri 63134, USA. jhwible@mkg.com
Troup
C M
CM
Hynes
M R
MR
Galen
K P
KP
MacDonald
J R
JR
Barco
S J
SJ
Wojdyla
J K
JK
Periasamy
M P
MP
Adams
M D
MD
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001773:Blood Cells; D002319:Cardiovascular System / Q000187:drug effects; D003287:Contrast Media / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005298:Fertility / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests
D003287:Contrast Media; D009942:Organometallic Compounds; C112666:gadoversetamide