Identification

Name
Danaparoid
Accession Number
DB06754
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Danaparoid is a low-molecular-weight heparinoid with an average molecular weight of 5500 Daltons consisting of a mixture of glycosaminoglycans [2]. The active constituents are heparan, dermatan and Chondroitin sulfate [4], and they are isolated from the porcine intestinal mucosa [Label]. Danaparoid possesses a potent antithrombic activity that works by inhibiting activated factor X (Factor Xa) and activated factor II (Factor IIa). It is chemically distinct from heparin by containing different protein binding properties, thus has lower cross-reactivity in heparin-intolerant patients. Danaproid is used in the treatment of heparin-induced thrombocytopenia (HIT) as an off-label indication and prevention of post-operative deep venous thrombosis (DVT). While it was initially approved by the FDA as Orgaran™, danaparoid was withdrawn by Organon International on August 14, 2002, due to a shortage in drug substance by the manufacturer. The use of Orgaran™ was discontinued in the United States however it is available in several other countries including European countries and Japan. Danaparoid sodium is the common salt form in therapeutic preparations and is typically administered subcutaneously.

Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Danaparoid sodium5004UU3156Not AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OrgaranSolution750 unitIntravenous; SubcutaneousAspen Pharmacare Canada Inc.1995-12-31Not applicableCanada
Categories
UNII
BI6GY4U9CW
CAS number
308068-55-5
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

Indicated for the prophylaxis of post-operative deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing elective hip replacement surgery [Label].

Associated Conditions
Pharmacodynamics

Danaparoid contains a mixture of heparan sulfate, dermatan sulfate and chondroitin sulfate in amounts of approximately 84%, 12% and 4%, respectively [3]. Danaparoid is as an antithrombotic agent that prevents the formation of fibrin in the coagulation pathway. It has a high antifactor Xa to antifactor IIa (thrombin) activity that primarily works via antithrombin III-mediated inhibition of factor Xa [3]. The ratio of antifactor Xa to antifactor II activity is ≥ 20:1 [3]. Danaparoid has a minor effect on platelet function and aggregation [Label]. In a worldwide compassionate-use programme involving a total of 667 patients with heparin-induced thrombocytopenia (HIT), treatment with danaparoid resulted in 93% of successful outcomes in resolving HIT [3].

In healthy volunteers, danaparoid caused significantly less prolongation o f the activated partial thromboplastin time (APTT) and was associated with a significantly lower thrombin time than unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) [3]. Danaparoid displays lower lipolytic activity than UFH in vitro and in healthy individuals, leading to lower plasma levels of free fatty acids [3]. Danaparoid has been associated with the cross-reactivity with pathogenic heparin-induced platelet-factor 4 (PF4) antibodies, which occurs in about 10 % or more by in vitro testing [1]. The clinical relevance of this effect is not fully understood [1].

Mechanism of action

In the coagulation cascade leading to clot formation, factor X and factor II requires activation to promote subsequent conversion of fibrinogen to fibrin. The mechanism of action of danaparoid resulting in anticoagulant and antithrombic effects involves a complex interaction between 2 components, factor IIa and in particular, factor Xa [3]. Via binding to antithrombin and inducing a conformational change [A32579], danaparoid enhances and catalyzes the the binding of factor Xa to antithrombin, which induces antithrombin-mediated inactivation of factor Xa. This leads to inhibition of thrombin generation and subsequently, thrombus formation [2]. Danaparoid also weakly enhances antithrombin III and heparin cofactor II inactivation of factor IIa [2]. There is evidence that danaparoid also suppresses the activation of factor IX which, in conjunction with simultaneous inhibition of factor X, may lead to antithrombic effects [3].

TargetActionsOrganism
AAntithrombin-III
positive allosteric modulator
Human
Absorption

Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly antifactor Xa and antifactor IIa activities. The bioavailability of danaparoid is 100% following subcutaneous administration [Label]. Following administration of single subcutaneous doses of 750, 1500, 2250, and 3250 anti-Xa units of danaparoid, the peak plasma anti-Xa activities were 102.4, 206.1, 283.9, and 403.4 mU/mL, respectively [Label]. The time to reach maximum anti-Xa activity is approximately 2-5 hours [Label].

Volume of distribution

Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The volumes of distribution of anti-Xa and anti-IIa activities are 9.1 L and 7.3-9.0 L, respectively [3].

Protein binding
Not Available
Metabolism

There is no evidence of hepatic metabolism and danaparoid is unlikely to undergo cellular metabolism [3].

Route of elimination

Renal excretion is the main route of elimination, accounting for approximately 40-50% of the total clearance of antifactor Xa activity following intravenous administration of danaparoid [3]. Therefore in patients with severe renal impairment, the elimination half-life of anti-Xa activity may be prolonged [Label].

Half life

Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The elimination half-life ranges from 19.2 to 24.5 hours during anti-Xa activity and ranges from 1.8 to 4.3 hours during anti-IIa activity [3].

Clearance

Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. Total plasma clearance is about 0.36 L/h during anti-Xa activity, which may be accelerated with higher body surface area [Label]. Total plasma clearance during anti-IIa activity ranges from 2.3 to 3 L [3].

Toxicity

Subcutaneous administration of a single dose at 3800 anti-Xa units/kg, which is 20.5 times the recommended dose for humans based on body surface area, was found to be lethal to female rats. Lethal effects were seen in male rats when administering a single subcutaneous dose at 15200 anti-Xa units/kg, which is approximately 82 times the recommended human dose based on body surface area [Label]. In rats, the symptoms of acute toxicity following intravenous administration included respiratory depression, prostration and twitching [Label].

Accidental overdosage of danaparoid may lead to severe bleeding complications. While protamine sulfate may partially neutralize the anti-Xa actions of danaparoid, there is no evidence that it is capable of reducing severe non-surgical bleeding during treatment of danaparoid. In case of serious bleeding, danaparoid should be discontinued and blood transfusions should be administered if necessary. Withdrawal of danaparoid is expected to restore the coagulation balance without rebound phenomenon [Label].

There is no evidence of danaparoid to have a potential to induce carcinogenesis, mutagenesis and impairment of fertility [Label].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Danaparoid can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Danaparoid is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Danaparoid is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Danaparoid can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Danaparoid can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Danaparoid is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Danaparoid can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Danaparoid can be increased when used in combination with 5beta-dihydrotestosterone.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Danaparoid.
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Danaparoid.
Food Interactions
Not Available

References

General References
  1. Kodityal S, Manhas AH, Udden M, Rice L: Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures. Eur J Haematol. 2003 Aug;71(2):109-13. [PubMed:12890149]
  2. Ibbotson T, Perry CM: Danaparoid: a review of its use in thromboembolic and coagulation disorders. Drugs. 2002;62(15):2283-314. [PubMed:12381232]
  3. Wilde MI, Markham A: Danaparoid. A review of its pharmacology and clinical use in the management of heparin-induced thrombocytopenia. Drugs. 1997 Dec;54(6):903-24. [PubMed:9421696]
  4. 24. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 299-300). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
External Links
PubChem Substance
347910366
Wikipedia
Danaparoid
ATC Codes
B01AB09 — Danaparoid
AHFS Codes
  • 20:12.04.16 — Heparins
FDA label
Download (566 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableCompletedNot AvailableAcute HIT II (Heparin-induced Thrombocytopenia Type II)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntravenous; Subcutaneous750 unit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Positive allosteric modulator
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory a...
Gene Name
SERPINC1
Uniprot ID
P01008
Uniprot Name
Antithrombin-III
Molecular Weight
52601.935 Da
References
  1. Liu J, Pedersen LC: Anticoagulant heparan sulfate: structural specificity and biosynthesis. Appl Microbiol Biotechnol. 2007 Feb;74(2):263-72. doi: 10.1007/s00253-006-0722-x. Epub 2006 Nov 28. [PubMed:17131147]

Drug created on September 14, 2010 10:20 / Updated on December 12, 2018 07:18