Idraparinux: Difference between revisions

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Idraparinux
Clinical data
Routes of; administration	Subcutaneous
ATC code	none;
Legal status
Legal status	Investigational;
Pharmacokinetic data
Elimination half-life	80-130 hours
Identifiers
	IUPAC name Nonasodium (2S,3S,4S,5R,6R)-6-[(2R,3R,4S,5R,6R)-6-; [(2R,3S,4S,5R,6R)-2-carboxylato-; 4,5-dimethoxy-6-[(2R,3R,4S,5R,6S)-6-methoxy-4,5-; disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]; oxyoxan-3-yl]oxy-4,5-disulfonatooxy-; 2-(sulfonatooxymethyl)oxan-3-yl]oxy-4,5-dimethoxy-; 3-[(2R,3R,4S,5R,6R)-3,4,5-trimethoxy-; 6-(sulfonatooxymethyl)oxan-2-yl]oxyoxane-; 2-carboxylate;
CAS Number	149920-56-9;
PubChem CID	3083444;
ChemSpider	2340656 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C38H55Na9O49S7
Molar mass	1727.17683 g/mol
3D model (JSmol)	Interactive image;
	SMILES CO[C@@H]1[C@H](O[C@@H]([C@@H]([C@H]1OC)OC)O[C@H]2[C@@H]([C@H]([C@@H](O[C@@H]2C(=O)[O-])O[C@@H]3[C@H](O[C@@H]([C@@H]([C@H]3OS(=O)(=O)[O-])OS(=O)(=O)[O-])O[C@H]4[C@@H]([C@H]([C@@H](O[C@H]4C(=O)[O-])O[C@@H]5[C@H](O[C@@H]([C@@H]([C@H]5OS(=O)(=O)[O-])OS(=O)(=O)[O-])OC)COS(=O)(=O)[O-])OC)OC)COS(=O)(=O)[O-])OC)OC)COS(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+];
	InChI InChI=1S/C38H64O49S7.9Na/c1-64-15-12(9-72-88(43,44)45)76-35(27(68-5)18(15)65-2)80-21-19(66-3)28(69-6)37(82-25(21)32(39)40)79-17-14(11-74-90(49,50)51)77-38(31(87-94(61,62)63)24(17)85-92(55,56)57)81-22-20(67-4)29(70-7)36(83-26(22)33(41)42)78-16-13(10-73-89(46,47)48)75-34(71-8)30(86-93(58,59)60)23(16)84-91(52,53)54;;;;;;;;;/h12-31,34-38H,9-11H2,1-8H3,(H,39,40)(H,41,42)(H,43,44,45)(H,46,47,48)(H,49,50,51)(H,52,53,54)(H,55,56,57)(H,58,59,60)(H,61,62,63);;;;;;;;;/q;9*+1/p-9/t12-,13-,14-,15-,16-,17-,18+,19+,20+,21+,22+,23+,24+,25+,26-,27-,28-,29-,30-,31-,34+,35-,36-,37-,38-;;;;;;;;;/m1........./s1 ; Key:MVPQUSQUURLQKF-MCPDASDXSA-E ;
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Revision as of 13:02, 3 December 2010

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

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Overview

Idraparinux sodium is a novel long-acting synthetic indirect inhibitor of coagulation factor Xa^[1]. The agent is being developed by Sanofi-Aventis. It has a similar chemical structure and mechanism of action as fondaparinux, but its elimination half-life of 80 hours is 5 to 6 times longer than that of fondaparix (17 hours). Given its long half life, it can be injected subcutaneously once a week.

Use in Atrial Fibrillation

The AMADEUS study

AMADEUS was a phase III, randomized, open label trial designed to compare the efficacy and safety of once-a-week idraparinux versus oral vitamin K antagonist (VKA) treatment for the long-term prevention of thromboembolic events (stroke and non-central nervous system systemic embolism)in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke. The predefined risk factors were previous ischemic stroke, transient ischemic attack or systemic embolization (SE), hypertension requiring drug treatment, left ventricular dysfunction, age >75 years, age between 65-75 years plus diabetes mellitus, or age between 65-75 years plus symptomatic coronary heart disease.

4,576 patients (2,283 in the idraparinux group and 2,293 in the VKA group) have been randomized between September 2003 and July 2005.

Patients with AF who were eligible for VKA treatment were randomized to receive either subcutaneous idraparinux 2.5 mg once a week or VKA therapy adjusted to achieve the target international normalized ratio (INR) of 2.5 (range 2 to 3). The study was powered to show non-inferior efficacy of idraparinux, compared with standard vitamin K antagonist (VKA) treatment in patients with AF who require prolonged oral anticoagulation. The primary efficacy endpoint was the composite of all strokes (ischemic, hemorrhagic and undefined) and non-CNS SE within the planned treatment period. The principal safety endpoint was the occurrence of major bleeding or clinically relevant non-major bleeding. The other safety outcome was all cause mortality. A weekly subcutaneous administration of idraparinux was as effective as warfarin, a Vitamin K Antagonist (VKA), in reducing stroke and non Central Nervous System (CNS) systemic embolic events in patients with atrial fibrillation (AF), a population at risk of thromboembolic events (TE). The results of the AMADEUS study were presented at the XXI ISTH Congress (International Society on Thrombosis and Haemostasis) in Geneva.

The AMADEUS trial, which enrolled a total of 4,576 patients with atrial fibrillation, met its primary endpoint. The event rate of the composite endpoint of any strokes (ischemic, hemorrhagic, and undefined) and non-CNS systemic embolism was 0.9% with idraparinux and 1.3% with warfarin (p= 0.007), meeting the criteria for non-inferiority.

The incidence of clinically relevant bleeding, the primary safety outcome, was significantly higher in the idraparinux group than in the comparator group (19.7% vs. 11.3%, p<0.0001), although, overall no difference was observed in the all causes mortality between the two treatment groups. Bleeding appeared over time and was more pronounced in patients with impaired renal function and in the elderly. These observations indicate the need to consider a dose reduction of idraparinux depending on these characteristics in patients with AF. This will be addressed in the new BOREALIS-AF study that will compare the new neutralizable form of idraparinux (biotinylated idraparinux) to VKA in patients with atrial fibrillation and in which the dose will be adjusted depending on age and renal function after 7 weeks of treatment.

Despite the early termination of the study due to the imbalance of bleeding events and low event rates, the trial succeeded in demonstrating the efficacy of idraparinux and met the criteria for non inferiority.With once a week idraparinux treatment we could have a convenient alternative to the cumbersome VKA treatment for patients suffering from atrial fibrillation recurrent complications.”' said Professor Harry Büller, from the University of Amsterdam’s Academic Medical Center Department of Vascular Medicine and principal investigator of the AMADEUS study. '“Nevertheless, the improvement of the safety profile while preserving efficacy should be addressed in the new BOREALIS-AF study with the once a week treatment with reversible biotinylated idraparinux, (a big step forward, well suited for a long acting agent) and dose adjustment according to patients characteristics.”' he added.

Biotinylated Version of Idraparinux

Because idraparinux has a very long half life, a biotinylated version of this drug (SSR 126517) is also in clinical development. The addition of a biotin moiety to the structure allows the more rapid removal of the drug upon the addition of avidin. A bioequipotency study of biotinylated idraparinux vs. idraparinux for the treatment of DVT is ongoing.

Biotinylated idraparinux is being compared to warfarin for the treatment of pulmonary embolism in the phase III CASSIOPEA.

The BOREALIS-AF study of Biotinylated Idraparinux

BOREALIS-AF is a multicenter, randomized, double-blind, assessor-blind, non-inferiority study comparing the efficacy and safety of once-a-week subcutaneous biotinylated idraparinux with adjusted-dose warfarin in the prevention of stroke and systemic thromboembolic events in patients with atrial fibrillation.

Treatment will be administrated for a period of 6 months to 2 years. All patients will start with biotinylated idraparinux 3 mg (equivalent to base idraparinux 2.5 mg) once-a-week for 7 weeks, and then the dose will be reduced depending on age and renal function.

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All cause death