Drugs

, Volume 45, Issue 2, pp 259–294

Defibrotide

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Vascular Disorders
  • Katharine J. Palmer
  • Karen L. Goa
Drug Evaluation

DOI: 10.2165/00003495-199345020-00007

Cite this article as:
Palmer, K.J. & Goa, K.L. Drugs (1993) 45: 259. doi:10.2165/00003495-199345020-00007
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Abstract

Synopsis

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use.

Trials performed to date have provided initial evidence that defibrotide is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis, while preliminary data suggest possible use in preventing fibrin deposition in the circuitry of renal haemodialysis equipment. Efficacy in preventing deep vein thrombosis after surgery has been demonstrated but defibrotide does not appear to offer any therapeutic advantage over heparin. Further clinical experience is required in other disorders, including acute myocardial infarction, Raynaud’s phenomenon, renal thrombotic microangiopathy and renal transplant rejection, before adequate assessment of efficacy in these areas can be made.

Defibrotide is well tolerated, as assessed in trials of up to 6 months duration, with a low global incidence of adverse events (<1 to 9%). Mild allergic reactions and gastrointestinal disturbances have occasionally been described, and a hypotensive effect has also infrequently been observed.

Thus, available data suggest that deflbrotide is a well tolerated agent with little or no anticoagulant activity, which is conveniently available in both parenteral and oral formulations. Initial data indicate that the drug may be a useful alternative in the treatment of peripheral obliterative arterial disease and thrombophlebitis, while its therapeutic potential in other vascular disorders and efficacy relative to established agents remains to be fully determined.

Pharmacodynamic Properties

Defibrotide appears to have a number of effects on mediators of the coagulation and fibrinolytic systems. The drug selectively stimulates prostaglandin I2 and E2 production and, therefore, increases blood levels of these prostanoids. This appears to be a selective action, as thromboxane A2 levels are unaffected. Defibrotide also increases the function of tissue plasminogen activator while decreasing that of plasminogen activator inhibitor, thus increasing fibrinolytic activity. Recent data indicate that defibrotide has some affinity for adenosine receptors, an action which may be responsible for the drug’s ability to increase prostaglandin I2 levels and prevent leucocyte activation and subsequent release of oxygen free radicals. Furthermore, a specific binding site for defibrotide on the vascular endothelium has recently been identified, although the clinical relevance of this has yet to be clarified.

Defibrotide appears to be largely devoid of anticoagulant properties as determined by a lack of clinically significant effects on coagulation parameters, including partial and activated thromboplastin times and prothrombin time. Data concerning the influence of defibrotide on specific clotting factors are incomplete, but the drug appears to have no effect on von Willebrand factor, factor VIII, factor Xa and prekallikrein, while its effects on antithrombin-III, fibrinogen and Protein C require further clarification. Defibrotide has been reported to have little effect on platelet numbers, but may inhibit platelet function, possibly by stimulating the formation of prostaglandin I2 or increasing platelet cyclic adenosine monophosphate levels.

Many of the pharmacodynamic effects of defibrotide are likely to be of clinical relevance. An increase in prostaglandin E2 and I2 levels may have therapeutic actions by causing regional vasodilation, inhibition of platelet aggregation and reduction of leukotriene B4 levels (a possible mediator of ischaemic damage). Inhibition of leucocyte activation may reduce the production of free radicals which may slow the progression of atheroma formation and prevent post-ischaemic damage.

Thus, animal studies have provided evidence that defibrotide has in vivo anti-ischaemic, antiatherosclerotic and antithrombotic effects. These studies have prompted clinical trials in a large number of vascular disorders and indicated potential uses of defibrotide in the future.

Pharmacokinetic Properties

Investigation of the pharmacokinetic behaviour of defibrotide is difficult because the drug is degraded in the body to a number of products and the identity of the active derivative in humans is unclear. To date, the majority of pharmacokinetic data have been determined by following the fate of the carbohydrate moiety of the drug, 6-deoxyribose, as a marker of the parent compound, although a recent study has used radiolabelled defibrotide. Due to these difficulties the data regarding the pharmacokinetics of defibrotide in humans (obtained from 23 healthy volunteers and 14 patients) are incomplete.

Intravenous injection of defibrotide 0.5 to 16 mg/kg in healthy volunteers results in a dose-dependent increase in plasma 6-deoxyribose concentrations. Steady-state plasma 6-deoxyribose concentrations of 25 to 68 mg/L were achieved after intravenous infusion of defibrotide (100 to 400 mg/h after a bolus injection of 200 to 400mg) or a single intravenous injection of 200mg. Plasma concentrations of 6-deoxyribose are maintained during the infusion period and subsequently decrease rapidly to basal concentrations at the end of infusion. The drug is absorbed after oral administration, giving maximum plasma concentrations of up to 7.8 mg/L 0.5 hours after a dose of [125I]defibrotide 423mg in patients with cancer. There does not appear to be any accumulation of defibrotide after repeated administration as areas under the plasma concentration-time curves were similar after the first and last doses administered to rats.

Volume of distribution values of 0.04 to 0.05 L/kg were obtained after intravenous administration of defibrotide 0.5 to 16 mg/kg to healthy volunteers. Data from animal studies indicate that after oral and intravenous administration the highest concentrations of defibrotide are found in the blood components, aorta, bone marrow, spleen, thyroid, adrenal glands and skin and highly perfused organs such as the liver and kidneys. The low bioavailability of defibrotide in humans (2.6 to 13%) may be due to uptake of the drug by the vascular endothelium.

Elimination of defibrotide in humans follows different kinetic models depending on the dose, with a 1-compartment model being the most appropriate following administration of low doses and a 2-compartment model better suited following high doses. The elimination half-life is short and increases with dose, with values of between 9.8 and 27.1 minutes after intravenous doses of 0.5 to 16 mg/kg or single intravenous injection of 200mg. The elimination half-life appears to be independent of route of administration with similar values being obtained after oral and intravenous administration. Animal and human studies have demonstrated that defibrotide is eliminated via the urine and the faeces, with a greater proportion of a radioactive dose undergoing renal elimination compared with biliary elimination following intravenous administration compared with oral administration. The mechanism of elimination is thought to consist of a non-saturable renal process and a saturable hepatic process.

Therapeutic Use

In patients with peripheral obliterative arterial disease defibrotide is effective in increasing absolute walking distance, a reliable measure of arterial sufficiency, with significant increases in the range 41 to 61% compared with baseline. Furthermore, defibrotide appears to be as effective as buflomedil and indobufen in improving this parameter. An improvement of regional limb blood flow has also been indicated. Despite the apparent efficacy of the drug in reducing symptoms of peripheral obliterative arterial disease, long term administration is required to determine whether defibrotide can influence the evolution and progression of the disease.

Significant decreases (43 to 99%) in the severity of symptoms of phlebitis, such as redness, pain, swelling and heat, have been reported following administration of defibrotide, indicating that the drug is an effective treatment in this indication. Comparative trials with heparin suggest that defibrotide shows similar efficacy to this established treatment. However, these encouraging data require further substantiation in trials using less subjective criteria of efficacy.

The use of defibrotide as an alternative to heparin in renal haemodialysis, especially in patients in whom heparin is contraindicated, has also been investigated. Preliminary results suggest that defibrotide is effective in preventing fibrin deposition in the circuitry of dialysis machines.

Despite encouraging initial data, the efficacy of defibrotide as a treatment for acute myocardial infarction, either as a monotherapy or in conjunction with standard thrombolytic agents, cannot be assessed as yet because of small patient numbers and a lack of comparative data. A similar lack of substantial data hampers assessment of the effect of defibrotide in renal disorders such as thrombotic microangiopathy and renal transplant rejection, and in Raynaud’s phenomenon. Defibrotide has been assessed as a prophylactic therapy against deep vein thrombosis and, although more effective than placebo, the drug does not appear to offer any therapeutic advantage over low dose heparin.

Tolerability

Defibrotide appears to be well tolerated with a global incidence of adverse events reported to range from < 1 to 9%. Adverse events were mostly mild and rarely resulted in patients withdrawing from treatment. An allergic reaction, characterised by sweating, tachycardia, rash, erythema and pruritus, has been described. The dermatological manifestation can be general or localised to the site of injection. A low incidence of gastrointestinal disturbance, such as nausea, vomiting and abdominal pain, and isolated occurrences of fever, headache, dizziness, palpitations, back pain and oedema have also been observed. A hypotensive effect has been reported in a limited number of patients.

Defibrotide has little or no effect on haemostatic components and, therefore, does not appear to have a major anticoagulant action. It has been shown to be associated with a lower incidence of operative and postoperative haemorrhagic complications than heparin.

Few data are available concerning the possible interaction of defibrotide with other drugs. However, caution is advised during the use of a combination of defibrotide and heparin as this treatment appears to result in a greater anticoagulant effect than the use of heparin alone.

Dosage and Administration

Defibrotide is available in intravenous, intramuscular and oral formulations. Parenteral routes of administration have been used during the treatment of disorders which require short term therapy and in haemodialysis patients, whereas the oral route has been used during long term treatment in order to improve patient acceptability.

The dosage of defibrotide administered for most disorders has commonly been between 400 and 1200 mg/day, with 800 mg/day the most frequently used. Higher dosages of up to 5.6 g/day have been administered for the treatment of acute myocardial infarction. Intravenous dosing regimens have consisted of an initial bolus injection followed by a slow infusion, and both parenteral and oral formulations have been divided into 2 to 4 doses. Defibrotide has been used as prophylaxis against the formation of deep vein thrombosis during and following surgery, with therapy commonly initiated the day before surgery.

Copyright information

© Adis International Limited 1993

Authors and Affiliations

  • Katharine J. Palmer
    • 1
  • Karen L. Goa
    • 1
  1. 1.Adis International LimitedAuckland 10New Zealand