Eltrombopag (SB-497 115) is a first-inclass, oral, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as oncedaily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dosedependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that el- IntroductionThrombocytopenia, a reduction in platelet count, is a frequent finding in several medical disorders, such as aplastic anemia, some infections, myelodysplasia, idiopathic thrombocytopenic purpura (ITP), and chronic liver disease. Another etiology of clinically significant thrombocytopenia is the use of myelosuppressive chemotherapy or interferon antiviral treatment. Currently, there is an unmet need for thrombopoietic agents for the treatment of thrombocytopenia.Thrombopoietin (Tpo) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor (TpoR) that is expressed on the surface of megakaryocytes, and megakaryocytic precursors. 1,2 Binding of Tpo to its receptor triggers the activation of the JAK-STAT pathway, leading to changes in gene expression that promote progression along the megakaryocytic pathway, ultimately leading to the release of platelets into the peripheral circulation. [3][4][5] Administration of recombinant Tpo to rodents, primates, and humans leads to significant increases in circulating platelet levels. [6][7][8][9][10][11] However, due to immunogenicity issues, forms of recombinant Tpo are no longer in clinical trials. Other molecules with Tpo-like activities are in clinical trials to treat thrombocytopenic patients. 13 Peptidyl thrombopoietic agents, such as AMG-531, have been shown to increase platelet counts in healthy volunteers 12 and patients with ITP 13 ; however, they are not orally bioavailable and they have the potential to be immunogenic. Nonpeptide, smallmolecule, TpoR agonists can be orally bioavailable and are less likely to induce an immune or injection site response. [14][15][16] In this report we describe a first-in-class, small-molecule, nonpeptide, orally bioavailable thrombopoietin receptor agonist, eltrombopag . Preclinical studies have shown that eltrombopag interacts selectively with TpoR, thereby activating intracellular signal transduction pathways, leading to increased proliferation and differentiation of human bone marrow progenitor cells. 17 Platelet counts increased when eltrombopag was administered as an oral suspension to chimpanzees. 18 Therefore, eltrombopag may be considered an oral platelet growth factor.This phase 1 clinical trial in healthy human subjects was conducted to assess the safety, tolerability, p...

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. WHAT THIS STUDY ADDS• Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed. AIMEltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. METHODSSubjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14. RESULTSCo-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,•) by 55% (42%, 69%) and Cmax by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects. CONCLUSIONSConcomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.