Preclinical safety assessment of Vasovist (Gadofosveset trisodium), a new magnetic resonance imaging contrast agent for angiography.
OBJECTIVE
Vasovist (EPIX Pharmaceuticals and Schering AG) is a newly developed blood pool contrast agent for magnetic resonance imaging with a high affinity for human albumin, making it an ideal tool for the detection of structural abnormalities such as stenosis and aneurysm. For the risk assessment of the single diagnostic use in patients, the toxicity of this compound was investigated.


METHODS
Studies of acute, repeated-dose, reproductive, and developmental toxicity as well as local tolerance, immunotoxicity, and mutagenic potential were performed.


RESULTS
Lethality was observed in rodents after single intravenous administration at doses of at least 2 orders of magnitude higher than the anticipated human dose of 0.03 mmol/kg. The no observed adverse effect level after repeated daily administration over the course of 4 weeks to monkeys exceeded the single diagnostic dose by a factor of 3.3. The main effect of repeated dosing in both rats and monkeys was vacuolation in kidney proximal tubules without concomitant effect on kidney function. Studies into reproduction toxicity have shown no evidence of effects on fertility or perinatal and postnatal development. Signs of embryo-fetal toxicity were observed in rabbits after repeated administration of high doses. No indications of immunotoxic and mutagenic effects were observed. In local tolerance testing, Vasovist was well tolerated after intravenous administration.


CONCLUSIONS
Vasovist was well tolerated with reasonable safety margins between the single diagnostic dose of 0.03 mmol/kg in humans and the doses resulting in adverse effects in animal studies.
Steger-Hartmann
Thomas
T
SCHERING AG, Experimental Toxicology, Berlin, Germany. thomas.stegerhartmann@schering.de
Graham
Philip B
PB
Müller
Simone
S
Schweinfurth
Hermann
H
D000014:Abnormalities, Drug-Induced; D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005298:Fertility / Q000187:drug effects; D005333:Fetus / Q000187:drug effects; D005682:Gadolinium; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016296:Mutagenesis / Q000187:drug effects; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D003287:Contrast Media; D009942:Organometallic Compounds; D005682:Gadolinium; C109932:gadofosveset trisodium