Details
Stereochemistry | ACHIRAL |
Molecular Formula | C25H22N4O4.2C2H7NO |
Molecular Weight | 564.6327 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 1 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NCCO.NCCO.CC1=NN(C(=O)\C1=N/NC2=C(O)C(=CC=C2)C3=CC(=CC=C3)C(O)=O)C4=CC=C(C)C(C)=C4
InChI
InChIKey=PLILLUUXAVKBPY-SBIAVEDLSA-N
InChI=1S/C25H22N4O4.2C2H7NO/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;2*3-1-2-4/h4-13,26,30H,1-3H3,(H,32,33);2*4H,1-3H2/b27-22-;;
Eltrombopag is a thrombopoietin (TPO) nonpeptide mimetic administered orally that activates the TPO receptor by binding to the transmembrane domain and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. Eltrombopag under brand name promacta is approved for the treatment of the 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 approved 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 and to treat patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28005311
Curator's Comment: Known to be CNS penetrant in mouse; bovine. Human data not available
Originator
Sources: http://www.ligand.com/news-events/press-releases/detail/227/ligand-partner-gsk-announces-record-quarterly
Curator's Comment: # GlaxoSmithKline (GSK) and Ligand Pharmaceuticals
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1864 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19642221 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | PROMACTA Approved UsePROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Limitations of Use: PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. PROMACTA is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Limitations of Use: PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. Treatment of Severe Aplastic Anemia PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Launch Date2008 |
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Primary | PROMACTA Approved UsePROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Limitations of Use: PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. PROMACTA is indicated for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Limitations of Use: PROMACTA should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. Treatment of Severe Aplastic Anemia PROMACTA is indicated for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Launch Date2008 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
7.03 μg/mL |
50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ELTROMBOPAG plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
101 μg × h/mL |
50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ELTROMBOPAG plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
21 h |
50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ELTROMBOPAG plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1% |
50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ELTROMBOPAG plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
300 mg 1 times / day multiple, oral Highest studied dose Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.1747 |
unhealthy, 52 n = 9 Health Status: unhealthy Condition: Thrombocytopenia Age Group: 52 Sex: M+F Population Size: 9 Sources: Page: p.1747 |
|
75 mg 1 times / day multiple, oral (max) Recommended Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Thrombocytopenia|Aplastic anemia Sources: Page: p.1 |
Disc. AE: Hepatic decompensation, Hepatotoxicity... AEs leading to discontinuation/dose reduction: Hepatic decompensation Sources: Page: p.1Hepatotoxicity Portal vein thrombosis |
50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Other AEs: Hemorrhage, Ataxia... Other AEs: Hemorrhage (serious, 3 patients) Sources: Ataxia (serious, 1 patient) Dyspnea (serious, 3 patients) Colitis (serious, 1 patient) Diarrhea (serious, 1 patient) Graft versus host disease (serious, 1 patient) Rash (serious, 1 patient) Seizure (serious, 1 patient) Cellulitis (serious, 1 patient) Hypoxia (serious, 1 patient) Infection (serious, 5 patients) Nausea (below serious, 12 patients) Abdominal pain (below serious, 1 patient) Ascites (below serious, 1 patient) Headache (below serious, 2 patients) Bilirubin increased (below serious, 10 patients) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Hepatic decompensation | Disc. AE | 75 mg 1 times / day multiple, oral (max) Recommended Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Thrombocytopenia|Aplastic anemia Sources: Page: p.1 |
Hepatotoxicity | Disc. AE | 75 mg 1 times / day multiple, oral (max) Recommended Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Thrombocytopenia|Aplastic anemia Sources: Page: p.1 |
Portal vein thrombosis | Disc. AE | 75 mg 1 times / day multiple, oral (max) Recommended Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Thrombocytopenia|Aplastic anemia Sources: Page: p.1 |
Abdominal pain | below serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Ascites | below serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Bilirubin increased | below serious, 10 patients | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Nausea | below serious, 12 patients | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Headache | below serious, 2 patients | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Ataxia | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Cellulitis | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Colitis | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Diarrhea | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Graft versus host disease | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Hypoxia | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Rash | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Seizure | serious, 1 patient | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Dyspnea | serious, 3 patients | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Hemorrhage | serious, 3 patients | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Infection | serious, 5 patients | 50 mg 1 times / day steady, oral Dose: 50 mg, 1 times / day Route: oral Route: steady Dose: 50 mg, 1 times / day Sources: |
unhealthy n = 39 Health Status: unhealthy Condition: Thrombocytopenia Population Size: 39 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 6.0 |
no | |||
Page: 50.0 |
weak | |||
Page: 30, 76 |
yes [IC50 2.7 uM] | yes (co-administration study) Comment: concurrent eltrombopag and rosuvastatin treatment resulted in increased rosuvastatin Cmax by 2.03-fold and AUC by 55% Page: 30, 76 |
||
Page: 54.0 |
yes [IC50 24.8 uM] | |||
Page: 38, 77 |
yes [IC50 3.5 uM] | |||
Page: 38, 77 |
yes [IC50 9.3 uM] | |||
Page: 16, 24 |
yes | |||
Page: 30.0 |
yes | |||
Page: 30.0 |
yes | |||
Page: 30.0 |
yes | |||
Page: 30.0 |
yes | |||
Page: 30.0 |
yes | |||
Page: 30.0 |
yes | |||
Page: 30.0 |
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 30.0 |
no | |||
Page: 30, 49 |
no | |||
Page: 21.0 |
yes | |||
Page: 5.0 |
yes | |||
Page: 5.0 |
yes | |||
Page: 5.0 |
yes | |||
Page: 5.0 |
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 8, 32 |
PubMed
Title | Date | PubMed |
---|---|---|
Eltrombopag: Is this "24 karat gold platelet" treatment for thrombocytopenia in cirrhosis associated with hepatitis C? | 2008 Apr |
|
Eltrombopag: an effective remedy for thrombocytopaenia? | 2008 Jun |
|
Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects. | 2011 Sep |
|
The biology of thrombopoietin and thrombopoietin receptor agonists. | 2013 Jul |
Patents
Sample Use Guides
Chronic Immune (Idiopathic) Thrombocytopenia: use the lowest dose of PROMACTA (eltrombopag) to achieve and maintain a platelet count greater than or equal to 50 x 109 /L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Initial Dose Regimen: Adult and Pediatric Patients 6 Years and Older with ITP: Initiate PROMACTA at a dose of 50 mg once daily, except in patients who are of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) or who have mild to severe hepatic impairment (Child-Pugh Class A, B, C). For patients of East Asian ancestry with ITP, initiate PROMACTA at a reduced dose of 25 mg once daily. For patients with ITP and mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, C), initiate PROMACTA at a reduced d ose of 25 mg once daily. For patients of East Asian ancestry with ITP and hepatic impairment (Child-Pugh Class A, B, C), consider initiating PROMACTA at a reduced dose of 12.5 mg once daily. Pediatric Patients with ITP Aged 1 to 5 Years: Initiate PROMACTA at a dose of 25 mg once daily. Monitoring and Dose Adjustment: After initiating PROMACTA, adjust the dose to achieve and maintain a platelet count greater than or equal to 50 x 109 /L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA and modify the dosage regimen of PROMACTA based on platelet counts as outlined in Table 1. During therapy with PROMACTA, assess CBCs with differentials, including platelet counts, weekly until a stable platelet count has been achieved. Obtain CBCs with differentials, including platelet counts, monthly thereafter. When switching between
Chronic Hepatitis C-associated Thrombocytopenia Use the lowest dose of PROMACTA to achieve and maintain a platelet count necessary to initiate and maintain antiviral therapy with pegylated interferon and ribavirin. Dose adjustments are based upon the platelet count response. Do not use PROMACTA to normalize platelet counts. In clinical trials, platelet counts generally began to rise within the first week of treatment with PROMACTA. Initial Dose Regimen: Initiate PROMACTA at a dose of 25 mg once daily. Monitoring and Dose Adjustment: Adjust the dose of PROMACTA in 25-mg increments every 2 weeks as necessary to achieve the target platelet count required to initiate antiviral therapy. Monitor platelet counts every week prior to starting antiviral therapy. During antiviral therapy, adjust the dose of PROMACTA to avoid dose reductions of peginterferon. Monitor CBCs with differentials, including platelet counts, weekly during antiviral therapy until a stable platelet count is achieved. Monitor platelet counts monthly thereafter. Do not exceed a dose of 100 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with PROMACTA.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22683680
It was investigated eltrombopag's effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotrans plant model. Eltrombopag increased peripheral human platelets and white blood cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41-, CD34- CD41+, and CD34- CD41- cells. For this purpose the cells were treated with 100ng/ml rhTPO or 3μg/ml eltrombopag for 10 to 60 minutes at 37°C. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34- C41+ cells, while eltrombopag had no effects on pSTAT3. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C78275
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EMA ASSESSMENT REPORTS |
REVOLADE (AUTHORIZED: PURPURA, THROMBOCYTOPENIC, IDIOPATHIC)
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EU-Orphan Drug |
EU/3/07/467
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1033040-24-2
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NON-SPECIFIC STEREOCHEMISTRY | |||
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C62501
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DTXSID80892349
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m4879
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DBSALT000063
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REVOLADE
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PRIMARY | APPROVED OCTOBER 2010 | ||
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100000093072
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4U07F515LG
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4U07F515LG
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QQ-15
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496775-62-3
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CHEMBL461101
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2127163-73-7
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ALTERNATIVE | |||
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735651
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PRIMARY | RxNorm | ||
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SUB30141
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ACTIVE MOIETY
PARENT (SALT/SOLVATE)
SUBSTANCE RECORD