There is an unmet need for thrombopoietic agents that can increase platelet counts in patients with thrombocytopenia. The development of recombinant versions of the main thrombopoietic hormone, thrombopoietin (Tpo), were terminated due to the unwanted formation of antibodies to endogenous thrombopoietin. Eltrombopag is an orally bioavailable, non-peptide, small molecule agonist of the thrombopoietin receptor that increases platelet counts in humans, by driving differentiation and proliferation of megakaryocytes. The development of eltrombopag as a treatment for thrombocytopenia involved iterative experiments in a series of in vitro and in vivo preclinical studies in which eltrombopag was shown to activate the Tpo receptor leading to signal transduction via the JAK-ST AT pathway in megakaryocyte cell lines, drive megakaryopoiesis in primary human bone marrow cells and increase platelet counts after oral administration to chimpanzees. The target exposure for increasing platelet counts was 30-90~g.h/ml, while the no observed adverse effect level was 164~g.h/ml. When administered to healthy subjects for 10 days, eltrombopag increased platelet counts in a dose dependent manner at doses of 30, 50 and 75mg, where exposures exceeded the predicted 30~g.h/ml. A Phase II study in adult subjects with chronic ITP showed that doses of 50mg and 75mg of eltrombopag increased platelet counts in up to 80% of subjects, compared to only 11 % of subjects that received placebo. Thorough characterization of the pharmacology of eltrombopag during preclinical and early clinical development allowed for data-driven dose selection decisions and provided a strong foundation for successful Phase III clinical studies and regulatory approval of eltrombopag as a much needed treatment for thrombocytopenic patients. Jenkins ABSTRACT Cardiovascular Medicine
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:580286 |
| Date | January 2011 |
| Creators | Jenkins, Julian |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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