Eltrombopag

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%.

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).

Description

ITP is an autoimmune disease in which antiplatelet antibodies accelerate the destruction of platelets. In addition, platelet production can be impaired because the antiplatelet antibodies can also damage megakaryocytes. Although the thrombocytopenia of ITP can be severe, signs of bleeding are usually only minor.
Eltrombopag is an oral, small-molecule, nonpeptide TPO-receptor agonist. It initiates TPO-receptor signaling by interacting with the transmembrane domain of the receptor, thereby inducing proliferation and differentiation of cells in the megakaryocytic lineage. Eltrombopag is the second TPO-receptor agonist to reach the market behind romiplostim (Nplate), a recombinant fusion protein launched in 2008. Both drugs are specifically indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is supplied as the ethanolamine salt (also known as eltrombopag olamine).
The most common adverse reactions associated with eltrombopag were nausea, vomiting, mennorrhagia, myalgia, paresthesia and cataracts. Eltrombopag is derived in five synthetic steps starting from 2-bromo-6-nitroanisole, via Suzuki coupling reaction with 3-carboxyphenylboronic acid to a biphenyl intermediate, followed by cleavage of the methyl ether moiety with hydrobromic acid, and reduction of the nitro group to an amino group under catalytic hydrogenation conditions. Subsequently, the amino group is diazotized with sodium nitrite and hydrochloric acid, and the diazonium intermediate is condensed with 1-(3,4-dimethylphenyl)-3-methyl-2,5-dihydro-1H-pyrazol-5-one to produce eltrombopag.

Chemical properties

Orange to Red Solid

Originator

Ligand Pharmaceuticals (US)

The Uses of Eltrombopag

Eltrombopag (SB-497115-GR, Promacta, Revolade) is a small molecule agonist of the c-mpl (TpoR) receptor with an IC50 of 0.69 μM for the inhibition of hERG K+ channel tail current. In preclinical studies, the compound was shown to interact selectively with

The Uses of Eltrombopag

An agonist of the Thrombopoietin (Tpo) receptor, used as treatment for thrombocytopenia.

Background

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.

Indications

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.

What are the applications of Application

Eltrombopag is an agonist of the c-Mpl (thrombopoietin receptor)

Definition

ChEBI: A hydrazine in which each nitrogen atom is substituted, one by a 3'-carboxy-2-hydroxy[1,1'-biphenyl]-3-yl group and the other by a 1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene group. A small molecule agonist of the c-mpl (TpoR) receptor (the physiological target of the hormone thrombopoietin), it has been developed as a medication for conditions that lead to thrombocytopenia (abnormally low platelet counts).

brand name

Promacta

Clinical Use

Thrombopoetin receptor agonist:
Treatment of chronic immune idiopathic thrombocytopenic purpura (ITP)
Chronic hepatitis C associated thrombocytopenia (HCV)
Severe aplastic anaemia

Synthesis

The synthesis of Eltrombopag is as follows:
At room temperature, add 8.02g (20.0mmol) compound of formula V, 3.98g (24.0mmol) 3-carboxyphenylboronic acid, 8.48g (80.0mmol) sodium carbonate, 1.46g (2.0mmol) PdCl2dppf into a 250mL three-necked flask, 80mL ethanol, 65mL water, nitrogen protection, heated to 80, reacted for 10h, cooled to room temperature, added 60mL water, filtered, the filtrate was adjusted to pH 1-2 with 2M hydrochloric acid, a red solid was precipitated, filtered, and the filter cake was ethanol/water ( v/v=1:1, 40mL) beating, filtering, and drying to obtain 7.58g, the yield is 85.8%, and the purity is 99.40%.

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: concentration of eltrombopag reduced.
Statins: increased rosuvastatin concentration, may need to reduce rosuvastatin dose.

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.

Metabolism

Mainly hepatically metabolised through cleavage, oxidation by cytochrome P450 isoenzymes CYP1A2 and CYP 2C8 and conjugation with glucuronic acid, glutathione, or cysteine.
Approximately 31% of a dose is eliminated in the urine as metabolites, and about 59% in the faeces (20% unchanged).

References

1) Xie?et al. (2018), Pharmacological characterization of eltrombopag, a novel orally active human thrombopoietin receptor agonist; J. Cell. Mol. Med.,?22?5367 2) Erickson-Miller?et al.?(2008),?Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist; Stem Cells,?27?424 3) Alvarado?et al.?(2019),?Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ; Blood,?133?2043 4) Guenther?et al.?(2019),?Eltrombopag promotes DNA repair in human hematopoietic stem and progenitor cells; Exp. Hematol.?73?1 5) Vlachodimitropoulou?et al.?(2017),?Eltrombopag: a powerful chelator of cellular or extracellular iron (II) alone or combined with a second chelator; Blood,?130?1923 6) Kao?et al.?(2018),?Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag; Science Transl. Med.,?10?eaas9563