IPRIVASK � desirudin
CANYON PHARMACEUTICALS, INC
DESCRIPTIONIprivask [Desirudin for Injection] is a specific inhibitor of human thrombin. It has aprotein structure that is similar to that of hirudin, the naturally occurring anticoagulantpresent in the peripharyngeal glands in the medicinal leech, Hirudo medicinalis.Hirudin is a single polypeptide chain of 65 amino acids residues and containsthree disulfide bridges. Desirudin has a chemical formula of C287H440N80O110S6with a molecular weight of 6963.52. Desirudin, which is expressed in yeast(Saccharomyces cerevisiae, strain TR 1456) by recombinant DNA technology differs fromthe natural hirudin by lack of a sulfate group on Tyr-63. The biological activity ofdesirudin is determined through a chromogenic assay which measures the ability ofdesirudin to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin incomparison to a desirudin standard. One vial of desirudin contains 15.75 mgdesirudin corresponding to approximately 315,000 antithrombin units (ATU) or20,000 ATU per milligram of desirudin with reference to the WHO InternationalStandard (prepared 1991) for alphathrombin.
Iprivask 15 mg is supplied as a sterile, white, freeze dried powder for injection. Eachvial contains 15.75 mg desirudin and the following inactive ingredients: 1.31 mganhydrous magnesium chloride USP, sodium hydroxide for injection USP. Eachprefilled syringe of diluent for Iprivask contains 0.6 mL sterile Mannitol USP (3%)in Water for Injection and is preservative free. See DOSAGE ANDADMINISTRATION section for reconstitution instructions. Iprivask 15 mg isadministered by subcutaneous (SC) injection, preferably at an abdominal or thigh site.To prepare the reconstituted aqueous solution, 0.5 mL of the mannitol diluent is addedunder aseptic conditions to the vial containing the sterile powder. Shaking gently rapidlydisperses the drug. The reconstituted solution has a pH of 7.4.STRUCTURAL FORMULA
Iprivask STRUCTURAL FORMULA
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CLINICAL PHARMACOLOGYMechanism of Action: Desirudin is a selective inhibitor of free circulating andclot-bound thrombin. The anticoagulant properties of desirudin are demonstrated by itsability to prolong the clotting time of human plasma. One molecule of desirudin binds toone molecule of thrombin and thereby blocks the thrombogenic activity of thrombin.As a result, all thrombin-dependent coagulation assays are affected. Activatedpartial thromboplastin time (aPTT) is a measure of the anticoagulant activity ofdesirudin and increases in a dose-dependent fashion. The pharmacodynamic effect ofdesirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. Amean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41)was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombintime (TT) frequently exceeds 200 seconds even at low plasma concentrations ofdesirudin, which renders this test unsuitable for routine monitoring of Iprivasktherapy. At therapeutic serum concentrations, desirudin has no effect on otherenzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin,tissue plasminogen activator, or activated protein C. In addition, it does not displayany effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin,or on complement activation by the classical or alternative pathways.
Pharmacokinetic PropertiesPharmacokinetic parameters were calculated based on plasma concentration dataobtained by a nonspecific ELISA method that does not discriminate between nativedesirudin and its metabolites. It is not known if the metabolites are pharmacologicallyactive.
Absorption: The absorption of desirudin is complete when subcutaneouslyadministered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneousadministration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of desirudinincreased to a maximum level (Cmax) between 1 and 3 hours. Both Cmax andarea-under-the-curve (AUC) values are dose proportional.
