How does Avatrombopag work in the body?

jnspharma

Avatrombopag, marketed as Doptelet, is an orally administered medication primarily used to treat thrombocytopenia (low platelet count) in adults with chronic liver disease who are scheduled for a medical or dental procedure, and in patients with chronic immune thrombocytopenia (ITP) who have not responded adequately to other treatments. Its mechanism of action revolves around stimulating the body's natural platelet production process.

To understand how avatrombopag works, it's essential to first grasp the role of thrombopoietin (TPO). TPO is a naturally occurring hormone, primarily produced in the liver, that acts as the main regulator of platelet production. It binds to specific receptors called thrombopoietin receptors (TPO-R), also known as c-Mpl, which are found on the surface of megakaryocytes and their progenitor cells in the bone marrow. Megakaryocytes are large cells in the bone marrow responsible for producing platelets. When TPO binds to its receptor, it triggers a cascade of intracellular signaling events that stimulate the proliferation (growth and multiplication) and differentiation (maturation) of these megakaryocyte progenitor cells, ultimately leading to an increased production of platelets.

Avatrombopag is classified as a thrombopoietin receptor agonist (TPO-RA). This means it mimics the action of endogenous TPO by binding to and activating the same TPO-R on megakaryocytes in the bone marrow. However, unlike TPO itself, avatrombopag is a small molecule that can be taken orally, offering a convenient treatment option.

Upon oral administration, Avapag 20 mg (Avatrombopag) is absorbed and travels through the bloodstream to the bone marrow. Once there, it selectively binds to the transmembrane domain of the TPO-R. This binding induces a conformational change in the receptor, initiating a series of downstream signaling pathways crucial for megakaryocyte development and platelet formation. Key pathways activated include:

JAK-STAT Pathway: Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins are essential in cellular growth and differentiation. Avatrombopag activates JAK proteins, which then phosphorylate STAT proteins. These phosphorylated STAT proteins dimerize and translocate to the cell nucleus, where they bind to specific DNA sequences and regulate the expression of genes involved in megakaryocyte proliferation and maturation.

MAPK Pathway (Mitogen-Activated Protein Kinase): This pathway is involved in controlling various cellular responses, including cell growth, proliferation, and differentiation. Avatrombopag's activation of the MAPK pathway further contributes to the robust production of platelets.

PI3K-Akt Pathway (Phosphoinositide 3-kinase-Protein Kinase B): This pathway plays a significant role in cell survival, growth, and metabolism. Its activation by avatrombopag supports the overall health and development of megakaryocytes, ensuring efficient platelet output.

By activating these critical signaling pathways, avatrombopag effectively "tells" the bone marrow to produce more megakaryocytes and, consequently, more platelets. The increase in platelet count is dose-dependent and typically becomes noticeable within 3 to 5 days of starting treatment, reaching peak levels around 10 to 13 days.

A notable feature of avatrombopag is its high specificity and affinity for the TPO-R. This minimizes the likelihood of it interacting with other cytokine receptors, which helps reduce the risk of unintended biological effects or off-target side effects.

From a pharmacokinetic standpoint, avatrombopag is rapidly absorbed after oral administration. It undergoes metabolism primarily by the cytochrome P450 enzymes CYP2C9 and CYP3A4 in the liver, with its metabolites mainly excreted in the feces. The elimination half-life of avatrombopag is approximately 19 hours, which allows for once-daily dosing.

In summary, avatrombopag works by acting as a thrombopoietin receptor agonist, directly stimulating the production of platelets in the bone marrow. It achieves this by binding to and activating the TPO-R on megakaryocyte progenitor cells, triggering intracellular signaling pathways that promote the proliferation and differentiation of these cells. This leads to an increase in circulating platelets, effectively managing thrombocytopenia and reducing the risk of bleeding in patients with chronic liver disease or chronic immune thrombocytopenia.