Prolonged Administration of Defibrotide Is Non-Immunogenic in Rats and Dogs.

Polyelectrolytes such as heparins and sulfated glycosaminoglycans are capable of interacting with endogenous proteins resulting in the generation of neoepitopes leading to the formation of antibodies such as the anti-heparin platelet factor 4 antibodies. Defibrotide represents a polyanionic, DNA derived antithrombotic/antiischemic drug which is currently used in the management of various blood and vascular disorders. Although defibrotide does not have the same protein binding profile as heparins, it mediates various cellular and plasmatic responses to produce its pharmacologic effects. The purpose of this study is to determine if the long term administration of defibrotide results in the generation of any antigenic responses in rats and dogs.

Individual groups of rats (n=24) and dogs (n=30) were administered intravenously with varying dosages of Defibrotide (0-4800 mg/kg/day in rats and 0-1600 mg/kg/day in dogs) for a 3 month period of time. At the end blood samples were drawn from each group and the collected sera were tested for the presence of anti-defibrotide, antiphospholipid and anti-heparin PF4 (HIT antibodies) using modified ELISA methods which utilized specific secondary antibodies (IgG-rat/dog conjugated to alkaline phosphatase) for the rat and dog plasmas. Blood samples collected from normal rats and dogs constituted the control group (n=30-40).

Neither the rats nor the dogs treated with Defibrotide exhibited any generation of anti-defibrotide, HIT and antiphospholipid antibodies in all groups of animals tested. There was no significant difference (p>0.05) between the control and defibrotide treated animals. The average circulating levels of defibrotide were dose dependent.

Prolonged administration of defibrotide to rats and dogs did not result in the production of antibodies to the drug product. Moreover, there was no evidence for the generation of HIT and antiphospholipid antibodies in these studies. Therefore, unlike heparins, defibrotide administration to animals does not lead to the generation of antibodies.

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