Defitelio: genotox, carcinogenicity and repro: done or skipped?

“Defibrotide was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay) nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”

“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”

“Exposure to defibrotide was associated with embryo-fetal toxicity (decreased number of implantations and viable fetuses compared to controls) in pregnant rabbits at doses approximately equivalent to the recommended clinical dose on a mg/m2 basis.”

“Defibrotide did not reduce hERG tail current at concentrations up to 500 μg/ml. ECG examinations were performed as part of a 13 week intravenous infusion toxicity study in dogs.”

“Defibrotide sodium was not mutagenic in vitro in a bacterial reverse mutation assay (Ames assay).”

“Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.”

“Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.”

“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”

“Recommendation: I concur with the pharmacology/toxicology reviewers that from a nonclinical perspective, Defitelio may be approved and that no additional nonclinical studies are needed to support approval”

“Defibrotide did not reduce hERG tail current at concentrations up to 500 μg/ml.”