Defibrotide

Defibrotide

Clinical data
Pregnancy category	X
Routes of administration	oral, i.m., i.v.
Legal status
Legal status	Rx only (where available)
Pharmacokinetic data
Bioavailability	58 - 70% orally (i.v. and i.m. = 100%)
Elimination half-life	t1/2-alpha = minutes; t1/2-beta = a few hours
Identifiers
CAS Number	83712-60-1
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Defibrotide is a deoxyribonucleic acid derivative (single stranded) derived from cow lung or porcine mucosa. It is an anticoagulant with a multiple mode of action (see below).

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).

Mode 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 sudies 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 is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries, but is currently not approved in the USA. The manufacturer is Gentium.

Usual indications

Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment OVD 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.

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.

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 myelosuppresive toxicity of melphalan. However, is too early for any definitive results at that stage.

Cautions and contraindications

• The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus.
• Pregnancy : The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist.
• Lactation : No human data is available. In order to avoid damage to the newborn, the nursing mother should either discontinue the drug or breastfeeding, taking into account the importance of treatment to the mother.
• Known Bleeding Disorders or Bleeding Tendencies having occurred recently : Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events.

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.

Usual doses

Doses of up to 5.6 grams per day have been used for the treatment of acute myocardial infarction. A daily dose of 800 mg intravenously or intramuscularly for 7-8 days starting 1 day preoperatively is usual given for the prevention of deep venous thrombosis. Doses of 400 to 1200 mg/day have been used for the treatment of peripheral obliterative arterial disease, thrombophlebitis, and Raynaud's phenomenon. The daily dose is divided into 2-4 doses.

A bolus of 100 mg to 400 mg intravenously given every hour or a continuous intravenous infusion to a total dose of 800 mg has been used during renal hemodialysis.

External references

• Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45:259-94.
• http://www.globalrx.com/medinfo/Defibrotide.htm
• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8747520&dopt=Abstract (Pharmacokinetic Aspects)
• http://www.gentium.it/Defibrotide.aspx (information provided by manufacturer)
• http://rx.onconews.org/news/Melphalan.html (on cytostatic combination therapy)
• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16252186&query_hl=3&itool=pubmed_docsum (Report from University of Istanbul regarding healing of VOC)