Identification

Name
Eltrombopag
Accession Number
DB06210
Description

Eltrombopag is used to treat low blood platelet counts in adults with chronic immune (idiopathic) thrombocytopenia (ITP), when certain other medicines, or surgery to remove the spleen, have not worked well enough. ITP is a condition that may cause unusual bruising or bleeding due to an abnormally low number of platelets in the blood. Eltrombopag has also been recently approved (late 2012) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 442.4666
Monoisotopic: 442.164105212
Chemical Formula
C25H22N4O4
Synonyms
  • Eltrombopag
  • Eltrombopagum
External IDs
  • SB 497115
  • SB-497115
  • SB497115

Pharmacology

Indication

Thrombopoietin receptor agonists are pharmaceutical agents that stimulate platelet production in the bone marrow. In this, they differ from the previously discussed agents that act by attempting to curtail platelet destruction.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics
Not Available
Mechanism of action

Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor. Eltrombopag is a stimulator of STAT and JAK phosphorylation. Unlike recombinant TPO or romiplostim, Eltrombopag does not activate the AKT pathway in any way. It should be noted that when given to patients with aplastic anemia, other lineages besides platelet count were increased, suggesting that either eltrombopag enhanced the effect of TPO in vivo; or there is a yet uncovered mechanism of action at work.

TargetActionsOrganism
UThrombopoietin receptor
agonist
Humans
Absorption

Peak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%.

Volume of distribution

Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations.

Protein binding

Eltrombopag is highly protein bound (>99%).

Metabolism

Eltrombopag is predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

Route of elimination

Eltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted.

Half-life

About 21-32 hours in healthy patients. About 26-35 hours in patients with idiopathic thrombocytopenic purpura.

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

Eltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation).

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Coagulation factor VFactor V Leiden(A;A) / (A;G)A alleleADR Directly StudiedPatients who carry this polymorphism in F5 are associated with an increased risk of thromboembolism when treated with eltrombopag.Details
Antithrombin-III---(T;T)C > TADR Directly StudiedPatients who carry this polymorphism in SERPINC1 are associated with antithrombin III deficiency and an increased risk of thromboembolism when treated with eltrombopag.Details

Interactions

Drug Interactions
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
AbacavirThe metabolism of Abacavir can be decreased when combined with Eltrombopag.
AbametapirThe serum concentration of Eltrombopag can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Eltrombopag can be increased when combined with Abatacept.
AbemaciclibEltrombopag may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AbirateroneThe serum concentration of Eltrombopag can be increased when it is combined with Abiraterone.
AcemetacinThe metabolism of Acemetacin can be decreased when combined with Eltrombopag.
AcenocoumarolThe metabolism of Eltrombopag can be decreased when combined with Acenocoumarol.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Eltrombopag.
Acetylsalicylic acidThe metabolism of Acetylsalicylic acid can be decreased when combined with Eltrombopag.
AcyclovirThe metabolism of Eltrombopag can be decreased when combined with Acyclovir.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid multivalent ions. Polyvalent cations in food or supplements will be chelated by eltrombopag; therefore, they should be separated by 4 hours before or 2 hours after taking eltrombopag.
  • Take on an empty stomach. Separate the administration of eltrombopag from food by at least 1 hour before and 2 hours after eating.

Products

Product Ingredients
IngredientUNIICASInChI Key
Eltrombopag olamine4U07F515LG496775-62-3PLILLUUXAVKBPY-SBIAVEDLSA-N
Product Images
International/Other Brands
Promacta / Revolade
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PromactaTablet, film coated25 mg/1OralGlaxosmithkline Inc2008-11-242019-04-30US flag00007 4640 13 nlmimage10 ed18f697
PromactaPowder, for suspension12.5 mg/1OralNovartis Pharmaceuticals Corporation2018-09-27Not applicableUS flag
PromactaTablet, film coated25 mg/1OralNovartis Pharmaceuticals Corporation2016-05-24Not applicableUS flag
PromactaPowder, for suspension25 mg/1OralGlaxosmithkline Inc2016-11-272016-11-28US flag
PromactaTablet, film coated75 mg/1OralGlaxosmithkline Inc2009-01-052019-03-31US flag00007 4642 13 nlmimage10 8c18c666
PromactaTablet, film coated75 mg/1OralNovartis Pharmaceuticals Corporation2016-04-01Not applicableUS flag
PromactaTablet, film coated12.5 mg/1OralNovartis Pharmaceuticals Corporation2016-08-22Not applicableUS flag
PromactaTablet, film coated100 mg/1OralGlaxosmithkline Inc2014-03-102016-11-28US flag
PromactaTablet, film coated50 mg/1OralGlaxosmithkline Inc2008-11-242019-04-30US flag00007 4641 13 nlmimage10 fd18fea7
PromactaPowder, for suspension25 mg/1OralNovartis Pharmaceuticals Corporation2018-09-27Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
B02BX05 — Eltrombopag
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Biphenyls and derivatives
Direct Parent
Biphenyls and derivatives
Alternative Parents
Benzoic acids / o-Xylenes / Phenylhydrazines / Benzoyl derivatives / 1-hydroxy-4-unsubstituted benzenoids / Pyrazolones / Monocarboxylic acids and derivatives / Hydrazones / Carboxylic acids / Azacyclic compounds
show 4 more
Substituents
1-hydroxy-4-unsubstituted benzenoid / Aromatic heteromonocyclic compound / Azacycle / Benzoic acid / Benzoic acid or derivatives / Benzoyl / Biphenyl / Carbonyl group / Carboxylic acid / Carboxylic acid derivative
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrazoles, hydrazines, benzoic acids (CHEBI:85010)

Chemical Identifiers

UNII
S56D65XJ9G
CAS number
496775-61-2
InChI Key
XDXWLKQMMKQXPV-QYQHSDTDSA-N
InChI
InChI=1S/C25H22N4O4/c1-14-10-11-19(12-15(14)2)29-24(31)22(16(3)28-29)27-26-21-9-5-8-20(23(21)30)17-6-4-7-18(13-17)25(32)33/h4-13,26,30H,1-3H3,(H,32,33)/b27-22-
IUPAC Name
3'-{2-[(4Z)-1-(3,4-dimethylphenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1-yl}-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
SMILES
CC1=NN(C(=O)\C1=N/NC1=CC=CC(C2=CC=CC(=C2)C(O)=O)=C1O)C1=CC=C(C)C(C)=C1

References

Synthesis Reference

http://doc.sciencenet.cn/upload/file/2011531154034454.pdf

General References
  1. Zekry A, Freiman J: Eltrombopag: Is this "24 karat gold platelet" treatment for thrombocytopenia in cirrhosis associated with hepatitis C? Hepatology. 2008 Apr;47(4):1418-21. doi: 10.1002/hep.22300. [PubMed:18366111]
  2. Mondelli MU: Eltrombopag: an effective remedy for thrombocytopaenia? J Hepatol. 2008 Jun;48(6):1030-2. doi: 10.1016/j.jhep.2008.03.008. Epub 2008 Mar 31. [PubMed:18433923]
  3. Tarantino MD, Fogarty P, Mayer B, Vasey SY, Brainsky A: Efficacy of eltrombopag in management of bleeding symptoms associated with chronic immune thrombocytopenia. Blood Coagul Fibrinolysis. 2013 Apr;24(3):284-96. doi: 10.1097/MBC.0b013e32835fac99. [PubMed:23492914]
  4. Kiang TK, Ensom MH, Chang TK: UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005 Apr;106(1):97-132. Epub 2005 Jan 12. [PubMed:15781124]
  5. Deng Y, Madatian A, Wire MB, Bowen C, Park JW, Williams D, Peng B, Schubert E, Gorycki F, Levy M, Gorycki PD: Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects. Drug Metab Dispos. 2011 Sep;39(9):1734-46. doi: 10.1124/dmd.111.040170. Epub 2011 Jun 6. [PubMed:21646437]
  6. Kuter DJ: The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013 Jul;98(1):10-23. doi: 10.1007/s12185-013-1382-0. Epub 2013 Jul 3. [PubMed:23821332]
  7. Eltrombopag [File]
KEGG Drug
D03978
PubChem Compound
9846180
PubChem Substance
175427059
ChemSpider
19879943
RxNav
711942
ChEBI
85010
ChEMBL
CHEMBL461101
ZINC
ZINC000011679756
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Eltrombopag
AHFS Codes
  • 20:16.00 — Hematopoietic Agents
FDA label
Download (197 KB)
MSDS
Download (33.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticIdiopathic Thrombocytopenic Purpura1
4CompletedTreatmentPurpura, Thrombocytopaenic, Idiopathic1
4Not Yet RecruitingTreatmentImmune Thrombocytopenia1
4RecruitingTreatmentAplastic Anemia1
4RecruitingTreatmentEltrombopag1
4RecruitingTreatmentHematological Neoplasms1
4RecruitingTreatmentPrimary Immune Thrombocytopenia1
4RecruitingTreatmentPrimary Immune Thrombocytopenia (ITP)1
4WithdrawnNot AvailableThrombocytopenia1
3Active Not RecruitingTreatmentSevere Aplastic Anemia (SAA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for suspensionOral12.5 mg/1
Powder, for suspensionOral25 mg/1
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral12.5 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral75 mg/1
Powder, for suspensionOral25 MG
TabletOral
Tablet, film coatedOral12.5 MG
Tablet, film coatedOral25 MG
Tablet, film coatedOral50 MG
Tablet, film coatedOral75 MG
Tablet, coatedOral50 mg
Tablet, film coated12.5 mg
Tablet, film coated25 mg
Tablet, film coated50 mg
Tablet
Tablet, coatedOral25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8052995Yes2011-11-082028-02-01US flag
US6280959Yes2001-08-282019-04-30US flag
US7790704Yes2010-09-072021-11-24US flag
US7452874Yes2008-11-182021-11-24US flag
US7473686Yes2009-01-062021-11-24US flag
US7160870Yes2007-01-092023-05-20US flag
US7795293Yes2010-09-142023-11-21US flag
US7547719Yes2009-06-162026-01-13US flag
US7332481Yes2008-02-192021-11-24US flag
US8062665Yes2011-11-222028-02-01US flag
US8052994Yes2011-11-082028-02-01US flag
US8071129Yes2011-12-062028-02-01US flag
US8052993Yes2011-11-082028-02-01US flag
US8828430Yes2014-09-092028-02-01US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityEltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0103 mg/mLALOGPS
logP4.02ALOGPS
logP6.03ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)3.97ChemAxon
pKa (Strongest Basic)-0.12ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area114.59 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity126.48 m3·mol-1ChemAxon
Polarizability47.7 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.6946
Blood Brain Barrier-0.6616
Caco-2 permeable-0.5811
P-glycoprotein substrateNon-substrate0.6578
P-glycoprotein inhibitor INon-inhibitor0.8297
P-glycoprotein inhibitor IINon-inhibitor0.9187
Renal organic cation transporterNon-inhibitor0.944
CYP450 2C9 substrateNon-substrate0.5991
CYP450 2D6 substrateNon-substrate0.8495
CYP450 3A4 substrateSubstrate0.5424
CYP450 1A2 substrateNon-inhibitor0.8173
CYP450 2C9 inhibitorInhibitor0.6357
CYP450 2D6 inhibitorNon-inhibitor0.8982
CYP450 2C19 inhibitorNon-inhibitor0.7625
CYP450 3A4 inhibitorNon-inhibitor0.7595
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6304
Ames testNon AMES toxic0.5993
CarcinogenicityNon-carcinogens0.5481
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.1796 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9862
hERG inhibition (predictor II)Non-inhibitor0.6936
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (91.2 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Details
1. Thrombopoietin receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
Receptor for thrombopoietin. May represent a regulatory molecule specific for TPO-R-dependent immune responses.
Gene Name
MPL
Uniprot ID
P40238
Uniprot Name
Thrombopoietin receptor
Molecular Weight
71244.08 Da
References
  1. Kuter DJ: Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193-206. [PubMed:19642221]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Kim TO, Despotovic J, Lambert MP: Eltrombopag for use in children with immune thrombocytopenia. Blood Adv. 2018 Feb 27;2(4):454-461. doi: 10.1182/bloodadvances.2017010660. [PubMed:29487060]
  2. Eltrombopag FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Kuter DJ: The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013 Jul;98(1):10-23. doi: 10.1007/s12185-013-1382-0. Epub 2013 Jul 3. [PubMed:23821332]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created on March 19, 2008 10:17 / Updated on September 17, 2020 23:28

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