NAV

Drotrecogin alfa

Identification

Summary

Drotrecogin alfa is a form of recombinant activated human protein C used to reduce mortality in patients with severe sepsis by inhibiting coagulation Factors V and VIII.

Generic Name
Drotrecogin alfa
DrugBank Accession Number
DB00055
Background

Drotrecogin alfa is activated human protein C that is synthesized by recombinant DNA technology. It is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond. Drotrecogin alfa was withdrawn from the market after a major study indicated that it was not effective in improving outcomes in patients with sepsis.

Type
Biotech
Groups
Approved, Investigational, Withdrawn
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Protein Chemical Formula
C1786H2779N509O519S29
Protein Average Weight
55000.0 Da
Sequences
>Heavy chain
LIDGKMTRRGDSPWQVVLLDSKKKLACGAVLIHPSWVLTAAHCMDESKKLLVRLGEYDLR
RWEKWELDLDIKEVFVHPNYSKSTTDNDIALLHLAQPATLSQTIVPICLPDSGLAERELN
QAGQETLVTGWGYHSSREKEAKRNRTFVLNFIKIPVVPHNECSEVMSNMVSENMLCAGIL
GDRQDACEGDSGGPMVASFHGTWFLVGLVSWGEGCGLLHNYGVYTKVSRYLDWIHGHIRD
KEAPQKSWAP
>Light chain
SKHVDGDQCLVLPLEHPCASLCCGHGTCIXGIGSFSCDCRSGWEGRFCQREVSFLNCSLD
NGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVKFPCGRPWKRMEKKRSHL
Download FASTA Format
Synonyms
  • Activated protein C
  • Blood coagulation factor XIV (human)
  • Drotrecogin alfa (activated)
  • Drotrecogin alfa (activated), lyophilized
  • Drotrecogin alfa activated
  • Drotrecogin alfa, activated
  • Drotrecogin-alfa
  • Recombinant human activated protein C (rH-APC)
External IDs
  • LY203638
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Pharmacology

Indication

For reduction of mortality in patients with severe sepsis.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Drotrecogin alfa is activated human protein C that is synthesized by recombinant DNA technology. It is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond. Drotrecogin alfa inhibits factor Va and VIIIa, thereby reducing the coagulability of blood.

Mechanism of action

Activated protein C combines with protein S on platelet surfaces and then degrades factor Va and factor VIIIa, thereby reducing blood coagulability.

TargetActionsOrganism
ACoagulation factor VIII
inhibitor
Humans
ACoagulation factor V
inhibitor
Humans
UPlasminogen activator inhibitor 1Not AvailableHumans
UThrombomodulinNot AvailableHumans
UVitamin K-dependent protein SNot AvailableHumans
UProthrombinNot AvailableHumans
UPlatelet factor 4Not AvailableHumans
UPlasma serine protease inhibitorNot AvailableHumans
USerpin B6Not AvailableHumans
UEndothelial protein C receptorNot AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

5.5 hours (mammalian reticulocytes, in vitro).

Clearance
  • 40 L/hr [severe sepsis adults]
  • 30 +/- 8 L/hr [patients without sepsis undergoing hemodialysis]
  • 28 +/- 9 L/hr [heathy]
Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Drotrecogin alfa.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Drotrecogin alfa.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Drotrecogin alfa is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Drotrecogin alfa is combined with Acenocoumarol.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Drotrecogin alfa.
Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XigrisInjection, powder, for solution5 mgIntravenousEli Lilly Nederland B.V.2016-09-082012-02-21EU flag
XigrisInjection, powder, lyophilized, for solution20 mg/10mLIntravenousEli Lilly & Co. Ltd.2001-11-242011-10-26US flag
XigrisInjection, powder, lyophilized, for solution5 mg/2.5mLIntravenousEli Lilly & Co. Ltd.2001-11-242011-10-26US flag
XigrisInjection, powder, for solution20 mgIntravenousEli Lilly Nederland B.V.2016-09-082012-02-21EU flag
Xigris (20mg/vial)Powder, for solution20 mg / vialIntravenousEli Lilly & Co. Ltd.2003-03-252011-11-14Canada flag

Categories

ATC Codes
B01AD10 — Drotrecogin alfa (activated)
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
JGH8MYC891
CAS number
98530-76-8

References

General References
Not Available
UniProt
P04070
Genbank
M11228
PubChem Substance
46505655
RxNav
352374
Therapeutic Targets Database
DAP000151
PharmGKB
PA131548935
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Drotrecogin_alfa
FDA label
Download (241 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Pancreatitis1
4CompletedTreatmentHematopoietic Stem Cell Transplantation (SCT) / Infection / Neoplasms, Hematologic / Sepsis1
4CompletedTreatmentSepsis2
4CompletedTreatmentSepsis / Septic Shock1
4CompletedTreatmentSeptic Shock1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • DSM Corp.
  • Eli Lilly & Co.
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous20 mg
Injection, powder, for solutionIntravenous5 mg
Injection, powder, lyophilized, for solutionIntravenous20 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous5 mg/2.5mL
Powder, for solutionIntravenous
Powder, for solutionIntravenous20 mg / vial
Powder, for solutionIntravenous5 mg / vial
Prices
Unit descriptionCostUnit
Xigris 20 mg vial1481.66USD vial
Xigris 5 mg vial370.42USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2139468No2007-08-212015-01-03Canada flag
CA2036894No2002-01-152011-02-22Canada flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.291Not Available
isoelectric point6.78Not Available

Targets

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Details1. Coagulation factor VIII
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Oxidoreductase activity
Specific Function
Factor VIII, along with calcium and phospholipid, acts as a cofactor for factor IXa when it converts factor X to the activated form, factor Xa.
Gene Name
F8
Uniprot ID
P00451
Uniprot Name
Coagulation factor VIII
Molecular Weight
267007.42 Da
References
  1. Geng JP, Castellino FJ: Properties of a recombinant chimeric protein in which the gamma-carboxyglutamic acid and helical stack domains of human anticoagulant protein C are replaced by those of human coagulation factor VII. Thromb Haemost. 1997 May;77(5):926-33. [Article]
  2. Colin G, Annane D: Corticosteroids and human recombinant activated protein C for septic shock. Clin Chest Med. 2008 Dec;29(4):705-12, x. doi: 10.1016/j.ccm.2008.06.009. [Article]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  4. Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS: Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood. 1984 Feb;63(2):486-9. [Article]
Details2. Coagulation factor V
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Copper ion binding
Specific Function
Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
Gene Name
F5
Uniprot ID
P12259
Uniprot Name
Coagulation factor V
Molecular Weight
251701.245 Da
References
  1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. [Article]
  2. Kanji S, Devlin JW, Piekos KA, Racine E: Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. Pharmacotherapy. 2001 Nov;21(11):1389-402. [Article]
  3. Lyseng-Williamson KA, Perry CM: Drotrecogin alfa (activated). Drugs. 2002;62(4):617-30; discussion 631-2. [Article]
  4. Joyce DE, Grinnell BW: Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med. 2002 May;30(5 Suppl):S288-93. [Article]
  5. Poe K: Drotrecogin alfa (activated) approved for treatment of severe sepsis. J Am Pharm Assoc (Wash). 2002 May-Jun;42(3):520-2. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS: Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood. 1984 Feb;63(2):486-9. [Article]
Details3. Plasminogen activator inhibitor 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major con...
Gene Name
SERPINE1
Uniprot ID
P05121
Uniprot Name
Plasminogen activator inhibitor 1
Molecular Weight
45059.695 Da
References
  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. [Article]
  2. Cerchiara E, Tirindelli MC, Giannetti B, Dicuonzo G, Avvisati G: [The numerous properties of the anticoagulant protein C]. Clin Ter. 2007 Mar-Apr;158(2):181-7. [Article]
  3. Idell S: Endothelium and disordered fibrin turnover in the injured lung: newly recognized pathways. Crit Care Med. 2002 May;30(5 Suppl):S274-80. [Article]
  4. Dhainaut JF, Yan SB, Margolis BD, Lorente JA, Russell JA, Freebairn RC, Spapen HD, Riess H, Basson B, Johnson G 3rd, Kinasewitz GT: Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis. Thromb Haemost. 2003 Oct;90(4):642-53. [Article]
Details4. Thrombomodulin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transmembrane signaling receptor activity
Specific Function
Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C ...
Gene Name
THBD
Uniprot ID
P07204
Uniprot Name
Thrombomodulin
Molecular Weight
60328.72 Da
References
  1. Gresele P, Agnelli G: Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci. 2002 Jan;23(1):25-32. [Article]
  2. Pineda AO, Chen ZW, Caccia S, Cantwell AM, Savvides SN, Waksman G, Mathews FS, Di Cera E: The anticoagulant thrombin mutant W215A/E217A has a collapsed primary specificity pocket. J Biol Chem. 2004 Sep 17;279(38):39824-8. Epub 2004 Jul 13. [Article]
  3. McCachren SS, Diggs J, Weinberg JB, Dittman WA: Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood. 1991 Dec 15;78(12):3128-32. [Article]
  4. Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K: Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. J Biochem. 1988 Feb;103(2):281-5. [Article]
  5. Boffa MC, Burke B, Haudenschild C: [Different localization of thrombomodulin]. Ann Biol Clin (Paris). 1987;45(2):191-7. [Article]
Details5. Vitamin K-dependent protein S
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Endopeptidase inhibitor activity
Specific Function
Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis.
Gene Name
PROS1
Uniprot ID
P07225
Uniprot Name
Vitamin K-dependent protein S
Molecular Weight
75121.905 Da
References
  1. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W: Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res. 2002 Mar 1;105(5):433-9. [Article]
  2. Hesselvik JF, Malm J, Dahlback B, Blomback M: Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost. 1991 Feb 12;65(2):126-9. [Article]
  3. Cosio FG, Harker C, Batard MA, Brandt JT, Griffin JH: Plasma concentrations of the natural anticoagulants protein C and protein S in patients with proteinuria. J Lab Clin Med. 1985 Aug;106(2):218-22. [Article]
Details6. Prothrombin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Omar MN, Shouk TA, Khaleq MA: Activity of blood coagulation and fibrinolysis during and after hydroxyethyl starch (HES) colloidal volume replacement. Clin Biochem. 1999 Jun;32(4):269-74. [Article]
  2. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W: Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res. 2002 Mar 1;105(5):433-9. [Article]
  3. Gruber A, Cantwell AM, Di Cera E, Hanson SR: The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo. J Biol Chem. 2002 Aug 2;277(31):27581-4. Epub 2002 Jun 17. [Article]
  4. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H, Hellings PW, Schaeffer P, Herbert JM, Collen D, Theilmeier G: The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med. 2002 Sep 2;196(5):565-77. [Article]
  5. Levi M, De Jonge E, van der Poll T: Recombinant human activated protein C (Xigris). Int J Clin Pract. 2002 Sep;56(7):542-5. [Article]
Details7. Platelet factor 4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Heparin binding
Specific Function
Released during platelet aggregation. Neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Che...
Gene Name
PF4
Uniprot ID
P02776
Uniprot Name
Platelet factor 4
Molecular Weight
10844.78 Da
References
  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. [Article]
Details8. Plasma serine protease inhibitor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Heparin-dependent serine protease inhibitor acting in body fluids and secretions. Inactivates serine proteases by binding irreversibly to their serine activation site. Involved in the regulation of...
Gene Name
SERPINA5
Uniprot ID
P05154
Uniprot Name
Plasma serine protease inhibitor
Molecular Weight
45674.315 Da
References
  1. Shen L, Villoutreix BO, Dahlback B: Involvement of Lys 62(217) and Lys 63(218) of human anticoagulant protein C in heparin stimulation of inhibition by the protein C inhibitor. Thromb Haemost. 1999 Jul;82(1):72-9. [Article]
  2. He X, Shen L, Bjartell A, Malm J, Lilja H, Dahlback B: The gene encoding vitamin K-dependent anticoagulant protein C is expressed in human male reproductive tissues. J Histochem Cytochem. 1995 Jun;43(6):563-70. [Article]
  3. Kobayashi H, Gabazza EC, Taguchi O, Wada H, Takeya H, Nishioka J, Yasui H, Kobayashi T, Hataji O, Suzuki K, Adachi Y: Protein C anticoagulant system in patients with interstitial lung disease. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1850-4. [Article]
  4. Hayashi T, Suzuki K: [Molecular biology of protein C-thrombomodulin pathway. Structure and function, and basic studies on its clinical application]. Nihon Rinsho. 1993 Jun;51(6):1610-9. [Article]
  5. Berg DT, Gerlitz B, Shang J, Smith T, Santa P, Richardson MA, Kurz KD, Grinnell BW, Mace K, Jones BE: Engineering the proteolytic specificity of activated protein C improves its pharmacological properties. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4423-8. Epub 2003 Apr 1. [Article]
Details9. Serpin B6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
May be involved in the regulation of serine proteinases present in the brain or extravasated from the blood (By similarity). Inhibitor of cathepsin G, kallikrein-8 and thrombin. May play an importa...
Gene Name
SERPINB6
Uniprot ID
P35237
Uniprot Name
Serpin B6
Molecular Weight
42621.575 Da
References
  1. Sun J, Coughlin P, Salem HH, Bird P: Production and characterization of recombinant human proteinase inhibitor 6 expressed in Pichia pastoris. Biochim Biophys Acta. 1995 Sep 27;1252(1):28-34. doi: 10.1016/0167-4838(95)00108-7. [Article]
Details10. Endothelial protein C receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Receptor activity
Specific Function
Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation.
Gene Name
PROCR
Uniprot ID
Q9UNN8
Uniprot Name
Endothelial protein C receptor
Molecular Weight
26671.245 Da
References
  1. Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H, Kimoto M: Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med. 1998 Apr 6;187(7):1029-35. [Article]
  2. Ruf W, Dorfleutner A, Riewald M: Specificity of coagulation factor signaling. J Thromb Haemost. 2003 Jul;1(7):1495-503. [Article]
  3. Castellino FJ, Liang Z, Volkir SP, Haalboom E, Martin JA, Sandoval-Cooper MJ, Rosen ED: Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. Thromb Haemost. 2002 Sep;88(3):462-72. [Article]
  4. Cerchiara E, Tirindelli MC, Giannetti B, Dicuonzo G, Avvisati G: [The numerous properties of the anticoagulant protein C]. Clin Ter. 2007 Mar-Apr;158(2):181-7. [Article]
  5. Liaw PC: Endogenous protein C activation in patients with severe sepsis. Crit Care Med. 2004 May;32(5 Suppl):S214-8. [Article]

Drug created at June 13, 2005 13:24 / Updated at January 02, 2024 23:41