Eltrombopag

Eltrombopag is a small-molecule thrombopoietin receptor agonist that binds to the transmembrane domain of the TPO receptor (c-Mpl) on megakaryocyte progenitor cells, triggering JAK2/STAT and MAPK signaling pathways that stimulate megakaryocyte proliferation, differentiation, and subsequent platelet production. Unlike endogenous TPO or romiplostim (which bind the extracellular domain), eltrombopag binds a distinct site, allowing it to be orally bioavailable. Clinical indications include: (1) chronic immune thrombocytopenia (ITP) in patients refractory to corticosteroids, IVIG, or splenectomy; (2) severe aplastic anemia, either as monotherapy in refractory cases or in combination with immunosuppressive therapy (cyclosporine + ATG) as first-line treatment; and (3) thrombocytopenia in chronic hepatitis C patients undergoing interferon-based therapy. Important pharmacologic considerations include chelation by polyvalent cations (calcium, iron, aluminum, magnesium) found in antacids, dairy, and mineral supplements, requiring spaced dosing. Hepatotoxicity is a key adverse effect, necessitating monitoring of liver function tests. Other risks include thromboembolism (due to excessive platelet stimulation), cataracts, and potential for bone marrow fibrosis with long-term use. Unlike thrombopoietin itself, eltrombopag does not cross-react with antibodies against endogenous TPO, making it useful even in patients with TPO-neutralizing antibodies. It is metabolized hepatically and should be used cautiously in patients with hepatic impairment, especially those of East Asian descent who have higher drug exposure.