The pharmacology and clinical application of thrombopoietin receptor agonists

Published on Sep 18, 2014in International Journal of Hematology2.245
· DOI :10.1007/S12185-014-1660-5
Caizheng Li1
Estimated H-index: 1
(Sichuan University),
Li Zheng1
Estimated H-index: 1
(Sichuan University)
Sources
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.
📖 Papers frequently viewed together
25 Citations
19 Citations
9 Citations
References91
Newest
#1Tomonori NakazatoH-Index: 21
#2Chisako ItoH-Index: 7
Last. Yoshinobu AisaH-Index: 17
view all 4 authors...
3 CitationsSource
Thrombocytopenia is a common finding in patients with chronic liver disease related to hepatitis C virus (HCV) infection. Interferon therapy may aggravate thrombopenia through the inhibition of platelet production, leading to premature discontinuation of therapy, dose reduction, and viral relapse. T
16 CitationsSource
#1J K Alkaabi (Sultan Qaboos University)H-Index: 3
#1J K Alkaabi (Sultan Qaboos University)H-Index: 1
Last. S M Balla (Sultan Qaboos University)H-Index: 1
view all 6 authors...
We present a case of a pregnant woman at 27 weeks of gestation with systemic lupus erythematosus who developed severe thrombocytopenia presenting with melena, epistaxis, gum bleeding and frank hematuria. She was resistant to most treatment modalities, including steroids, intravenous immunoglobulins (IVIG), rituximab, IV cyclophosphamide and eltrombopag. She responded to romiplostim with normalization of her platelet count, which enabled her to be delivered safely at 34 weeks of gestation.
38 CitationsSource
#1Matthew J. Olnes (NIH: National Institutes of Health)H-Index: 16
#2Phillip ScheinbergH-Index: 44
Last. Cynthia E. DunbarH-Index: 80
view all 14 authors...
Background Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. Methods We conducted ...
313 CitationsSource
#1Takumi Kawaguchi (Kurume University)H-Index: 44
#2Atsumasa KomoriH-Index: 31
Last. Michio Sata (Kurume University)H-Index: 90
view all 13 authors...
Background Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD).
21 CitationsSource
#1Mary Beth Wire (RTP: Research Triangle Park)H-Index: 18
#2Jennifer Bruce (RTP: Research Triangle Park)H-Index: 1
Last. Andres Brainsky (GSK: GlaxoSmithKline)H-Index: 12
view all 7 authors...
Abstract Background Bioavailability of the tablet formulation of eltrombopag, an oral thrombopoietin receptor agonist indicated for the treatment of chronic immune thrombocytopenia, is reduced by chelation of polyvalent cations (eg, calcium). A powder for oral suspension (PfOS) formulation has been developed for use in pediatrics. Objective We aimed to assess the bioavailability of eltrombopag PfOS relative to the tablet formulation and the effect of a high-calcium meal on PfOS bioavailability. ...
27 CitationsSource
#1P. VorobyevH-Index: 2
#2L. KrasnovaH-Index: 1
Last. O. BorisenkoH-Index: 2
view all 3 authors...
1 CitationsSource
#1Siobhan HayesH-Index: 2
#2Daniele Ouellet (RTP: Research Triangle Park)H-Index: 26
Last. Ekaterina GibianskyH-Index: 9
view all 5 authors...
The relationship between plasma eltrombopag concentrations and increases in platelet counts (PLTC) was characterized in healthy volunteers (HVs) and patients with immune thrombocytopenic purpura (ITP) using population pharmacokinetic/pharmacodynamic (PK/PD) models. The semiphysiological model included 3 PK, 1 precursor production, 2 maturation, and 1 blood platelet compartments and assumed a linear increase in platelet production rate with eltrombopag concentrations. Thrombopoiesis was assumed t...
27 CitationsSource
#1Yanli Deng (GSK: GlaxoSmithKline)H-Index: 6
#2Armina MadatianH-Index: 2
Last. Peter D. GoryckiH-Index: 10
view all 11 authors...
The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men after a single oral administration of a solution dose of [14C]eltrombopag (75 mg, 100 μCi). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity). A mono-oxygenation metabolite (M1) and acyl glucuronides (M2) of eltrombopag were ...
28 CitationsSource
#1Yukari Shirasugi (Tokai University)H-Index: 11
#2Kiyoshi Ando (Tokai University)H-Index: 53
Last. Richard Lizambri (Amgen)H-Index: 7
view all 14 authors...
The efficacy and safety of romiplostim, a thrombopoietin-mimetic peptibody, were evaluated in a double-blind, placebo-controlled, randomized trial of Japanese patients with chronic immune thrombocytopenia (ITP). Thirty-four ITP patients received romiplostim (n = 22) or placebo (n = 12) for 12 weeks, with a starting romiplostim dose of 3 μg/kg weekly. The primary end point was the number of weeks with platelet response, defined as a platelet count ≥50 × 109/L (not including the 4 weeks after resc...
72 CitationsSource
Cited By6
Newest
#1Xiaowei FuH-Index: 1
Last. Weidong XiaoH-Index: 3
view all 8 authors...
ABSTRACT Since its introduction in 1991, laparoscopic splenectomy (LS) has become the gold standard in elective spleen surgery in many centres. However, there still lack the report of long-term outcomes of LS with the large-scale cases. The aim of the present study was to analyze the short- and long-term outcomes of LS in a single institution over 16 years, and to compare the perioperative outcomes of totally laparoscopic splenectomy (TLS) and hand-assisted laparoscopic splenectomy (HALS) for sp...
Source
#1Chunlu Li (CDUTCM: Chengdu University of Traditional Chinese Medicine)H-Index: 1
#2Xiaoxuan LiH-Index: 3
Last. Jianming WuH-Index: 3
view all 9 authors...
Background: Avatrombopag is a novel oral, nonpeptide thrombopoietin receptor agonist (TPO-RA). A few studies have shown that avatrombopag is effective against thrombocytopenia. However, no systematic review has been conducted on the efficacy and safety of avatrombopag. Therefore, the aim of this study was to comprehensively assess the efficacy and safety of avatrombopag patients with thrombocytopenia. Methods: Databases including Medline, PubMed, Embase, the Cochrane Library and ClinicalTrials.g...
4 CitationsSource
#1Chengying Xie (CAS: Chinese Academy of Sciences)H-Index: 13
#2Huajun Zhao (ZJNU: Zhejiang Chinese Medical University)H-Index: 1
Last. Liguang Lou (CAS: Chinese Academy of Sciences)H-Index: 17
view all 5 authors...
: Nonpeptide thrombopoietin receptor (TPOR/MPL) agonists, such as eltrombopag, have been used to treat thrombocytopenia of various aetiologies. Here, we investigated the pharmacological properties of hetrombopag, a new orally active small-molecule TPOR agonist, in preclinical models. Hetrombopag specifically stimulated proliferation and/or differentiation of human TPOR-expressing cells, including 32D-MPL and human hematopoietic stem cells, with low nanomolar EC50 values through stimulation of ST...
5 CitationsSource
#1Huan-Di Liu (Xinxiang Medical University)H-Index: 1
#2Ai-Jie Zhang (Fudan University Shanghai Medical College)H-Index: 1
Last. Yi-Chun Zhu (Fudan University Shanghai Medical College)H-Index: 26
view all 5 authors...
Background Our previous pilot studies aimed to examine the role of hydrogen sulfide (H2S) in the generation of endothelial progenitor cells led to an unexpected result, i.e., H2S promoted the differentiation of certain hematopoietic stem/progenitor cells in the bone marrow. This gave rise to an idea that H2S might promote hematopoiesis.
5 CitationsSource
#1Angelica Maria Garzon (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 1
#2William Beau Mitchell (Cornell University)H-Index: 7
Most children with immune thrombocytopenia (ITP) will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long-term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA) have been shown to be safe and efficacious in adults with ITP, and represent a...
13 CitationsSource
#1Akihito FujimiH-Index: 9
#2Yusuke KamiharaH-Index: 11
Last. Junji Kato (Sapporo Medical University)H-Index: 40
view all 12 authors...
A 55-year-old female with stage IVA follicular lymphoma in third complete remission underwent allogeneic peripheral blood stem cell transplantation. Neutrophil engraftment was achieved on day +18; however, platelet counts remained below 10 × 103/µL, necessitating transfusions twice a week for more than 3 months. Bone marrow showed a decreased number of megakaryocytes with hypolobulated nuclei. No graft versus host disease, viral infection, or disease relapse was observed. Furthermore, severe thr...
13 CitationsSource