Defibrotide

Pharmacokinetics

Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailability is in the range of 58-70% of the parenteral forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral radiolabelled defibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug's short half-life, it is necessary to give the daily dose divided in 2 to 4 doses (see below).

Mechanism of action

The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator (tPA-)function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent studies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).

Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g., hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision.

The drug was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. In the USA it is marketed as Defitelio. The manufacturer is Gentium.

Approvals and indications

Defibrotide is used to treat or prevent a failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment, VOD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated.

In April 2016 the US FDA approved it for the treatment of hepatic VOD after hematopoietic stem cell transplantation (HSCT).

Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud's phenomenon. In very high doses, defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments.

Experimental

It has been investigated for use in treatment of chronic venous insufficiency.

Potential indications in the future

Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area.

Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus melphalan, prednisone, and thalidomide in patients with multiple myeloma have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.

Cautions and contraindications

Side-effects

Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far.

Drug interactions

Use of heparin with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of serious bleeding will be increased considerably.