Skip to main content

Advertisement

SpringerLink
Log in

The pharmacology and clinical application of thrombopoietin receptor agonists

  • Review Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

The discovery and application of thrombopoietin (TPO) and thrombopoietin receptor (TPOR) agonists have changed the clinical treatment of thrombocytopenia. These compounds exert favorable clinical effects without the adverse events caused by traditional treatments (e.g., corticosteroids, immunoglobulins, monoclonal antibodies and splenectomy). This review provides a synopsis of new agents that boost platelet production, especially the TPOR agonists, and highlights their pharmacological characteristics and clinical applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood. 2001;97(9):2549–54.

    Article  CAS  PubMed  Google Scholar 

  2. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88(1):3–40.

    CAS  PubMed  Google Scholar 

  3. George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost. 2006;4(8):1664–72.

    Article  CAS  PubMed  Google Scholar 

  4. Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994;77(7):1117–24.

    Article  CAS  PubMed  Google Scholar 

  5. de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, et al. Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature. 1994;369:533–8.

    Article  PubMed  Google Scholar 

  6. Stoffel R, Wiestner A, Skoda RC. Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood. 1996;87:567–73.

    CAS  PubMed  Google Scholar 

  7. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA. 1994;91:11104–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Peck-Radosavljevic M, Zacherl J, Meng YG, Pidlich J, Lipinski E, Längle F, et al. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver? J Hepatol. 1997;27:127–31.

    Article  CAS  PubMed  Google Scholar 

  9. Debili N, Wendling F, Cosman D, Titeux M, Florindo C, Dusanter-Fourt I, et al. The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood. 1995;85(2):391–401.

    CAS  PubMed  Google Scholar 

  10. Li J, Xia Y, Kuter DJ. Interaction of thrombopoietin with the platelet c-mpl receptor in plasma: binding, internalization, stability and pharmacokinetics. Br J Haematol. 1999;106:345–56.

    Article  CAS  PubMed  Google Scholar 

  11. Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87(10):4068–71.

    CAS  PubMed  Google Scholar 

  12. Fielder PJ, Gurney AL, Stefanich E, Marian M, Moore MW, Carver-Moore K, et al. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood. 1996;87(6):2154–61.

    CAS  PubMed  Google Scholar 

  13. Wolber EM, Jelkmann W. Thrombopoietin: the novel hepatic hormone. News Physiol Sci. 2002;17:6–10.

    CAS  PubMed  Google Scholar 

  14. Geddis AE, Linden HM, Kaushansky K. Thrombopoietin: a pan-hematopoietic cytokine. Cytokine Growth Factor Rev. 2002;13(1):61–73.

    Article  CAS  PubMed  Google Scholar 

  15. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100(10):3457–69.

    Article  CAS  PubMed  Google Scholar 

  16. Kaushansky K, Drachman JG. The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production. Oncogene. 2002;21(21):3359–67.

    Article  CAS  PubMed  Google Scholar 

  17. Majka M, Ratajczak J, Villaire G, Kubiczek K, Marquez LA, Janowska-Wieczorek A, et al. Thrombopoietin, but not cytokines binding to gp130 protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normal human CD34(+) cells, megakaryocytes, and platelets. Exp Hematol. 2002;30(7):751–60.

    Article  CAS  PubMed  Google Scholar 

  18. Schulze H, Ballmaier M, Welte K, Germeshausen M. Thrombopoietin induces the generation of distinct Stat1, Stat3, Stata5a and Stat5b homo- and heterodimeric complexes with different kinetics in human platelets. Exp Hematol. 2000;28(3):294–304.

    Article  CAS  PubMed  Google Scholar 

  19. Ezumi Y, Takayama H, Okuma M. Thrombopoietin, c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonist-induced aggregation of platelets in vitro. FEBS Lett. 1995;374(1):48–52.

    Article  CAS  PubMed  Google Scholar 

  20. Rojnuckarin P, Drachman JG, Kaushansky K. Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood. 1999;94(4):1273–82.

    CAS  PubMed  Google Scholar 

  21. Drachman JG, Sabath DF, Fox NE, Kaushansky K. Thrombopoietin signal transduction in purified murine megakaryocytes. Blood. 1997;89(2):483–92.

    CAS  PubMed  Google Scholar 

  22. Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Demetri GD. Targeted approaches for the treatment of thrombocytopenia. Oncologist. 2001;6(5):15–23.

    Article  CAS  PubMed  Google Scholar 

  24. Kuter DJ. Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia. Annu Rev Med. 2009;60:193–206.

    Article  CAS  PubMed  Google Scholar 

  25. Basser RL, O’Flaherty E, Green M, Edmonds M, Nichol J, Menchaca DM, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99(7):2599–602.

    Article  CAS  PubMed  Google Scholar 

  26. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12):3241–8.

    Article  CAS  PubMed  Google Scholar 

  27. Peeters K, Stassen JM, Collen D, Van Geet C, Freson K. Emerging treatments for thrombocytopenia: increasing platelet production. Drug Discov Today. 2008;13(17–18):798–806.

    Article  CAS  PubMed  Google Scholar 

  28. Wang T, Wang Z, Yang R. Thrombopoietic growth factors in the treatment of immune thrombocytopenic purpura. Crit Rev Oncol Hematol. 2011;77(3):172–83.

    Article  PubMed  Google Scholar 

  29. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76(6):628–38.

    Article  CAS  PubMed  Google Scholar 

  30. Bussel JB, Kuter DJ, Phil D, George JN, McMillan R, Aledort LM, et al. AMG531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355(16):1672–81.

    Article  CAS  PubMed  Google Scholar 

  31. Lam MS. Review article: Second-generation thrombopoietin agents for treatment of chronic idiopathic thrombocytopenic purpura in adults. J Oncol Pharm Pract. 2010;16:89–103.

    Article  CAS  PubMed  Google Scholar 

  32. Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, et al. Phase 1 clinical study of eltrombopag, an oral, non-peptide thrombopoietin receptor agonist. Blood. 2007;109:4739–41.

    Article  CAS  PubMed  Google Scholar 

  33. Nichol JL. AMG 531: an investigational thrombopoiesis-stimulating pepti-body. Pediatr Blood Cancer. 2006;47:723–5.

    Article  PubMed  Google Scholar 

  34. Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25(2):52–60.

    Article  CAS  PubMed  Google Scholar 

  35. Kim MJ, Park SH, Opella SJ, Marsilje TH, Michellys PY, Seidel HM, et al. NMR structural studies of interactions of a small, nonpeptidyl Tpo mimic with the thrombopoietin receptor extracellular juxtamembrane and transmembrane domains. J Biol Chem. 2007;282:14253–61.

    Article  CAS  PubMed  Google Scholar 

  36. Bussel JB, Pinheiro MP. Eltrombopag. Cancer Treat Res. 2011;157:289–303.

    Article  CAS  PubMed  Google Scholar 

  37. Erickson-Miller CL, DeLorme E, Tian SS, Hopson CB, Stark K, Giampa L, et al. Discovery and characterization of a selective, non-peptidyl thrombopoietin receptor agonist. Exp Hematol. 2005;33:85–93.

    Article  CAS  PubMed  Google Scholar 

  38. Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, Toomey JR. Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol. 2009;37:1030–7.

    Article  CAS  PubMed  Google Scholar 

  39. Erickson-Miller CL, Delorme E, Tian SS, Hopson CB, Landis AJ, Valoret EI, et al. Preclinical activity of eltrombopag (SB-497115), an oral nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27(2):424–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Nplate (romiplostim) [prescribing information]. Thousand Oaks, Calif: Amgen Inc; 2008. http://www.nplate.com/patient/pdf/nplate_pi.pdf. Accessed Aug 17 2009.

  41. Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood. 2007;109(11):4739–41.

    Article  CAS  PubMed  Google Scholar 

  42. Gibiansky E, Zhang J, Williams D, Wang Z, Ouellet D. Population pharmacokinetics of eltrombopag in healthy subjects and patients with chronic idiopathic thrombocytopenic purpura. J Clin Pharmacol. 2011;51:842–56.

    Article  CAS  PubMed  Google Scholar 

  43. Hayes S, Ouellet D, Zhang J, Wire MB, Gibiansky E. Population PK/PD modeling of eltrombopag in healthy volunteers and patients with immune thrombocytopenic purpura and optimization of response-guided dosing. J Clin Pharmacol. 2011;51(10):1403–17.

    Article  CAS  PubMed  Google Scholar 

  44. Wire MB, Bruce J, Gauvin J, Pendry CJ, McGuire S, Qian Y, et al. A randomized, open-label, 5-period, balanced crossover study to evaluate the relative bioavailability of eltrombopag powder for oral suspension (PfOS) and tablet formulations and the effect of a high-calcium meal on eltrombopag pharmacokinetics when administered with or 2 h before or after PfOS. Clin Ther. 2012;34(3):699–709.

    Article  CAS  PubMed  Google Scholar 

  45. FDA Label approved on 11/20/2008 for PROMACTA,NDA no.022291 [EB/OL]. http://www.fda.gov/cder/foi/label/2008/022291lbl.pdf.

  46. Deng Y, Madatian A, Wire MB, Bowen C, Park JW, Williams D, et al. Metabolism and disposition of eltrombopag, an oral, non-peptide thrombopoietin receptor agonist, healthy human subjects. Drug Metab Dispos. 2011;39(9):1734–46.

    Article  CAS  PubMed  Google Scholar 

  47. Newland A, Caulier MT, Kappers-Klunne M, Schipperus MR, Lefrere F, Zwaginga JJ, et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol. 2006;135:547–53.

    Article  PubMed  Google Scholar 

  48. Shirasugi Y, Ando K, Hashino S, Nagasawa T, Kurata Y, Kishimoto Y, et al. A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura. Int J Hematol. 2009;90(2):157–65.

    Article  CAS  PubMed  Google Scholar 

  49. Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet. 2008;371:395–403.

    Article  CAS  PubMed  Google Scholar 

  50. Shirasugi Y, Ando K, Miyazaki K, Tomiyama Y, Okamoto S, Kurokawa M, Kirito K, et al. Romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial. Int J Hematol. 2011;94:71–80.

    Article  CAS  PubMed  Google Scholar 

  51. Kumagai Y, Fujita T, Ozaki M, Sahashi K, Ohkura M, Ohtsu T, et al. Pharmacodynamics and pharmacokinetics of AMG 531, a thrombopoiesis-stimulating peptibody, in healthy Japanese subjects: a randomized, placebo-controlled study. J Clin Pharmacol. 2007;47:1489–97.

    Article  CAS  PubMed  Google Scholar 

  52. Aledort LM, Hayward CPM, Chen M-G, Nichol JL, Bussel JB. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating anti-thrombopoietin antibodies. Am J Hematol. 2004;76:205–13.

    Article  CAS  PubMed  Google Scholar 

  53. Dower WJ, Cwirla SE, Balasubramanian P, Schatz PJ, Baccanari DP, Barrett RW. Peptide Agonists of the Thrombopoietin Receptor. Stem Cells. 1998;16(Suppl 2):21–9.

    Article  PubMed  Google Scholar 

  54. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237–47.

    Article  CAS  PubMed  Google Scholar 

  55. Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641–8.

    Article  CAS  PubMed  Google Scholar 

  56. Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377:393–402.

    Article  CAS  PubMed  Google Scholar 

  57. Saleh MN, Bussel JB, Cheng G, Meddeb B, Mayer B, Bailey C, et al. Long-term treatment of chronic immune thrombocytopenic purpura with oral eltrombopag: results from the extend study. 51st annual meeting of the american-society-of-hematology. Blood. 2010;116(21):37–8.

    Google Scholar 

  58. Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, Toomey JR. Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol. 2009;37(9):1030–7.

    Article  CAS  PubMed  Google Scholar 

  59. Kantarjian H, O’Brien S, Ravandi F, Cortes J, Shan J, Bennett JM, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer. 2008;113(6):1351–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Kantarjian HM, Giles FJ, Fenaux P, Becker PS, Boruchov AM, Bowen DT, et al. Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study. J Clin Oncol 2007 ASCO Annual Meeting Proceedings. 25 (18 Suppl) 7032.

  61. Kantarjian HM, Giles FJ, Greenberg PL, Paquette RL, Wang ES, Gabrilove JL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010;116(17):3163–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Sekeres MA, Kantarjian H, Fenaux P, Becker P, Boruchov A, Guerci-Bresler A, et al. Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer. 2011;117(5):992–1000.

    Article  CAS  PubMed  Google Scholar 

  63. Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, et al. Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009;114(18):3899–908.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Erickson-Miller CL, Kirchner J, Aivado M, May R, Payne P, Chadderton A. Reduced proliferation of non-megakaryocytic acute myelogenous leukemia and other leukemia and lymphoma cell lines in response to eltrombopag. Leuk Res. 2010;34(9):1224–31.

    Article  CAS  PubMed  Google Scholar 

  65. Shiffman ML, Ghany MG, Morgan TR, Wright EC, Everson GT, Lindsay KL, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132:103–12.

    Article  CAS  PubMed  Google Scholar 

  66. McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, et al. Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. N Engl J Med. 2007;357:2227–36.

    Article  CAS  PubMed  Google Scholar 

  67. Kawaguchi T, Komori A, Seike M, Fujiyama S, Watanabe H, Tanaka M, et al. Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study. J Gastroenterol. 2012;47(12):1342–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Elting LS, Rubenstein EB, Martin CG, Kurtin D, Rodriguez S, Laiho E, et al. Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia. J Clin Oncol. 2001;19:1137–46.

    CAS  PubMed  Google Scholar 

  69. Natale R, Charu V, Schuette W, Albert I, Tehenes S, McCoy J, et al. Safety of romiplostim for treatment of chemotherapy-induced thrombocytopenia (CIT) in patients with advanced non-small cell lung cancer (NSCLC). 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology; 2009 Sep 20–24; Berlin, GERMANY. EJC Supplement 2009; 7(2):574–574.

  70. Fanale M, Stiff P, Noonan K, McCoy J, Rutstein M, Moskowitz C. Safety of romiplostim for treatment of severe chemotherapy induced thrombocytopenia (CIT) in patients with lymphoma receiving multi-cycle chemotherapy: results from an open-label dose- and schedule-finding study. 15th Congress of the European-Cancer-Organization/34th Multidisciplinary Congress of the European-Society-for-Medical-Oncology; 2009 Sep 20-24; Berlin, GERMANY. EJC Supplement, 2009; 7(2):563–563.

  71. Kellum A, Jagiello-Gruszfeld A, Bondarenko IN, Patwardhan R, Messam C. Mostafa Kamel Y. A randomized, double-blind, placebo-controlled, dose ranging study to assess the efficacy and safety of eltrombopag in patients receiving carboplatin/paclitaxel for advanced solid tumors. Curr Med Res Opin. 2010;26(10):2339–46.

    Article  CAS  PubMed  Google Scholar 

  72. Alkaabi JK, Alkindi S, Riyami NA, Zia F, Balla LM, Balla SM. Successful treatment of severe thrombocytopenia with romiplostim in a pregnant patient with systemic lupus erythematosus. Lupus. 2012;21(14):1571–4.

    Article  CAS  PubMed  Google Scholar 

  73. Voican CS, Naveau S, Perlemuter G. Successful antiviral therapy for hepatitis C virus-induced cirrhosis after an increase in the platelet count with romiplostim: two case reports. Eur J Gastroenterol Hepatol. 2012;24(12):1455–8.

    Article  CAS  PubMed  Google Scholar 

  74. Cela I, Miller IJ, Katz RS, Rizman A, Shammo JM. Successful treatment of amegakaryocytic thrombocytopenia with eltrombopag in a patient with systemic lupus erythematosus (SLE). Clin Adv Hematol Oncol. 2010;8(11):806–9.

    PubMed  Google Scholar 

  75. Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia. N Engl J Med. 2012;367(1):11–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Lin B, Renshaw MW, Autote K, Smith LM, Calveley P, Bowdish KS, et al. A step-wise approach significantly enhances protein yield of a rationally-designed agonist antibody fragment in E. coli. Protein Expr Purif. 2008;59(1):55–63.

    Article  CAS  PubMed  Google Scholar 

  77. Frederickson S, Renshaw MW, Lin B, Smith LM, Calveley P, Springhorn JP, et al. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Proc Natl Acad Sci USA. 2006;103:14307–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Cerneus D, Brown K, Harris R, End D, Molloy C, Yurkow E, et al. Stimulation of platelet production in healthy volunteers by a novel pegylated peptide-based thrombopoietin (TPO) receptor agonist. 47th Annual Meeting of the American-Society-of-Hematology; 2005 Dec 10-13; Atlanta, GA. Blood. 2005;106(11):363A–4A.

    Google Scholar 

  79. Samtani MN, Perez-Ruixo JJ, Brown KH, Cerneus D, Molloy CJ. Pharmacokinetic and pharmacodynamic modeling of pegylated thrombopoietin mimetic peptide (PEG-TPOm) after single intravenous dose administration in healthy subjects. J Clin Pharmacol. 2009;49:336–50.

    Article  CAS  PubMed  Google Scholar 

  80. Suzuki K, Abe M, Fukushima-Shintani M, Sugasawa K, Hirayama F, Kawasaki T, et al. YM477, a novel orally-active thrombopoietin receptor agonist. 47th Annual Meeting of the American-Society-of-Hematology; 2005 Dec 10–13; Atlanta, GA. Blood. 2005;106(11):647A–647A.

    Google Scholar 

  81. Fukushima-Shintani M, Suzuki K, Iwatsuki Y, Abe M, Sugasawa K, Hirayama F, et al. AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis. Exp Hematol. 2008;36:1337–42.

    Article  CAS  PubMed  Google Scholar 

  82. Desjardins RE, Tempel DL, Lucek R, Kuter DJ. Single and multiple oral doses of AKR-501 (TM477) increase the platelet count in healthy volunteers. 48th Annual Meeting of the American-Society-of-Hematology; 2006 Dec 09–12; Orlando FL. Blood. 2006;108(11):145A–145A.

    Google Scholar 

  83. Bussel JB, Zhang J, Tang S, McIntosh J, Kater DJ. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial on the Efficacy, Safety and Tolerability of E5501 (AKR501) In Subjects with Chronic Immune Thrombocytopenia (ITP). 52nd Annual Meeting of the American-Society-of-Hematology (ASH); 2010 Dec 04-07; Orlando, FL.Blood 2010:116:38–38.

  84. Bussel JB, Zhang J, Tang S, McIntosh J, Kater DJ. Efficacy, Safety and Tolerability of E5501 (AKR501) In a 6-Month Extension Study In Subjects with Chronic Immune Thrombocytopenia (ITP). 52nd Annual Meeting of the American-Society-of-Hematology (ASH); 2010 Dec 04–07; Orlando, FL. Blood 2010; 116(21):1516–1516.

  85. Fox NE, Lim J, Chen R, Geddis AE. F104S c-Mpl responds to a transmembrane domain-binding thrombopoietin receptor agonist: proof of concept that selected receptor mutations in congenital amegakaryocytic thrombocytopenia can be stimulated with alternative thrombopoietic agents. Exp Hematol. 2010;38:384–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Dziewanowska ZE, Matsumoto RM, Zhang JK, Schindler K, Loewen G, Doherty JP, et al. Single and multiple oral doses of LGD-4665, a small molecule thrombopoietin receptor agonist, increase platelet counts in healthy male subjects. 49th Annual Meeting of the American-Society-of-Hematology; 2007 Dec 08–11; Atlanta, GA. Blood 2007; 110(11): 390A.

  87. Kai M, Motoki K, Yoshida H, Emuta C, Chisaka Y, Tsuruhata K, et al. Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor. Nat Biotechnol. 2008;26:209–11.

    Article  CAS  PubMed  Google Scholar 

  88. Sanz MA, Aledort L, Mathias SD, Wang X, Isitt JJ. Analysis of EQ-5D scores from two phase 3 clinical trials of romiplostim in the treatment of immune thrombocytopenia (ITP). Value Health. 2011;14(1):90–6.

    Article  PubMed  Google Scholar 

  89. Dranitsaris G, Tsang P. Eltrombopag or intravenous immunoglobulin as a bridge to splenectomy in adults with chronic idiopathic thrombocytopenic purpura: a canadian economic analysis (abstracts). Clin Lymphoma Myeloma Leuk. 2010;10(3):E26–E26.

    Article  CAS  Google Scholar 

  90. Vorobyev PA, Krasnova L, Borisenko O. Clinical and Economic Analysis of Eltrombopag in Chronic Idiopathic Thrombocytopenic Purpura in Context of Russian Health Care System. Value in Health 2011.A416.

  91. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161–71.

    Article  CAS  PubMed  Google Scholar 

  92. Nakazato T, Ito C, Mihara A, Aisa Y. Successful treatment of eltrombopag-resistant refractory immune thrombocytopenia with romiplostim. Int J Hematol. 2013;97(2):291–3.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Mr. Li and Dr. Zheng were responsible for the literature search, collection and interpretation of the data, figure collection, writing and final approval of the manuscript. The authors wish to thank Dr. Liang and Dr. Miao for their assistance.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Caizheng Li & Li Zheng

Authors
  1. Caizheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Zheng.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, C., Zheng, L. The pharmacology and clinical application of thrombopoietin receptor agonists. Int J Hematol 100, 529–539 (2014). https://doi.org/10.1007/s12185-014-1660-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1660-5

Keywords

Search

Navigation