Avatrombopag, an oral thrombopoietin receptor agonist: results of two double‐blind, dose‐rising, placebo‐controlled Phase 1 studies

Kuter, David J.; Allen, Lee F.

doi:10.1111/bjh.15574

Cited by 24 publications

(20 citation statements)

References 13 publications

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“…155,156 The drug is administered orally, has no interactions with food or cations, does not require monitoring of liver functions, and is three-to fourfold more potent than eltrombopag in stimulating an increase in platelets in healthy volunteers. 157,158 Phase 2 studies in humans showed that 93% of adult ITP patients had a platelet response (platelets increasing to .50 3 10 9 /L) 7 days after starting a 20-mg/d dose vs 7% of those on placebo. 159 Responses were maintained for 6 months in an extension study.…”

Section: Subsequent Therapy: Medicalmentioning

confidence: 99%

Updated international consensus report on the investigation and management of primary immune thrombocytopenia

et al. 2019

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Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

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Section: Subsequent Therapy: Medicalmentioning

confidence: 99%

Updated international consensus report on the investigation and management of primary immune thrombocytopenia

et al. 2019

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“…As per the results of 2 double-blind, dose-rising, placebo-controlled phase-I studies in healthy adults reported by Kuter and Allen, 73 63 individuals who fulfilled the required criteria were registered to a single-dose study of avatrombopag (1, 3, 10, 20, 50, 75, and 100 mg) and 9 participants were assigned to each of these doses, whereas in each cohort, 6 participants took avatrombopag while the remaining 3 of them used placebo. In the multiple-dose study population, 29 subjects were assigned, in which 9, 11, and 9 subjects were assigned to 3, 10, and 20 mg cohort studies, respectively.…”

Section: Clinical Evaluation Of Avatrombopag (Ym 477 Akr-501 and E5mentioning

confidence: 79%

“…72 Therefore, these in vitro and in vivo data illustrated significant therapeutic value of avatrombopag for the management of various thrombocytopenias that are associated with ITP, CLD, and cancer chemotherapeutic drugs. 73…”

Section: In Vitro and In Vivo Preclinical Evaluation Of The Activitiementioning

confidence: 99%

Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag

Abdela

2019

Clin Med�Insights�Blood�Disord

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Chronic liver disease (CLD) is a condition that progresses over time toward advanced disease state which is known as liver cirrhosis. Liver cirrhosis leads to dangerous health problems among people living across the world. One such problem that observed in about 75% of cirrhotic patients is thrombocytopenia; which in turn associated with poor prognosis and recovery from CLD. Beyond these, thrombocytopenia in cirrhotic patients led to impairment of coagulation cascade and significantly influenced the utilization of effective mechanism in the management of CLD. By nature, treatment of CLD involves invasive diagnostic and treatment procedures; therefore, in the presence of thrombocytopenia implementing these methods put the lives of patients in a critical health problem due to increased risk of bleeding and mortality. Because of these reasons, prophylactic transfusion of platelets is considered to be one of the most effective options that reduce the risk of bleeding in patients with CLD that required to undergo an invasive procedure. Although platelet transfusion presented with significant advantages in facilitating the invasive procedure in patients with CLD, refractoriness with repeated use and various problems associated with its transfusion limit the continuous utilization of this important option. With these challenges and current advance in the knowledge of thrombopoiesis, the development of relatively safe and alternative drugs that enhance the production of platelets by interacting with thrombopoietin receptor agonists provides a promising option to platelet transfusion. The discovery and approval of romiplostim and eltrombopag in August 2008 and November 2008, respectively, for the treatment of chronic immune thrombocytopenia paved a way and followed by the Food and Drug Administration (FDA) approval of 2 potentially advantageous drugs, lusutrombopag, and avatrombopag, in 2018 for the treatment of thrombocytopenia in patients with CLD that required to undergo elective surgery. Therefore, this review aims to assess pathogenesis of thrombocytopenia and its challenges in the management of liver-related issues and, more importantly, gives emphasis to address the potential use of avatrombopag in the treatment of thrombocytopenia underlying CLD, its pharmacokinetics and pharmacodynamics, as well as its toxicological profiles by presenting the most commonly reported adverse events in various trials.

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“…Similar to other TPO receptor agonists, this binding results in a cascade of cellular events through signal transduction by activating various signaling mediators and finally megakaryocyte differentiation into platelets. 39,40 Avatrombopag is indicated in the treatment of patients with ITP who have failed prior therapies. In addition, unlike eltrombopag, avatrombopag was also approved for treatment of thrombocytopenia in adult patients with CLD who are scheduled to undergo an invasive procedure (►Table 1).…”

Section: Avatrombopagmentioning

confidence: 99%

Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease

Khemichian

Terrault

2020

Semin Thromb Hemost

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Thrombocytopenia is one of the most common hematologic complications in cirrhosis. Despite limited data linking platelet count and bleeding risk in patients with cirrhosis, the use of platelets transfusions for invasive procedures has been a common practice. Recently, thrombopoietin (TPO) receptor agonists have been approved for use in patients with chronic liver disease (CLD) undergoing invasive procedures. The aim of this study was to review current literature on bleeding risk in patients with cirrhosis and the use of platelet transfusions and TPO receptor agonists in the context of invasive procedures. PubMed search was conducted to find articles relating to cirrhosis, thrombocytopenia, and new novel treatments for this condition. Search terms included CLD, cirrhosis, thrombocytopenia, bleeding, thrombosis, coagulopathy, hemostasis, and TPO receptor agonists. Romiplostim, eltrombopag, avatrombopag, and lusutrombopag are approved TPO receptor agonists, with avatrombopag and lusutrombopag specifically approved for use in patients with CLD undergoing invasive procedures. In patients with platelet counts < 50,000/mm3, avatrombopag and lusutrombopag increased the platelet counts above this threshold in the majority of treated patients and reduced the frequency of platelet transfusions. At the approved doses, incidence of thrombosis was not increased and therapies were well tolerated. Studies were not powered to assess whether risk of bleeding complications was reduced and the fundamental question of whether correction of thrombocytopenia is warranted in patients undergoing invasive procedures remains unanswered. The use of TPO receptor agonists has resulted in less requirement for platelet transfusions. In patients with cirrhosis undergoing invasive procedures for whom platelet transfusion is planned, TPO receptor agonists are an alternative and avoid the risks associated with transfusions. However, there is need for a thoughtful approach to manage bleeding risk in patients with cirrhosis undergoing procedures, with the consideration of a comprehensive hemostatic profile, the severity of portal hypertension, and the complexity of the invasive procedure to guide decisions regarding transfusions or use of TPO receptor agonists.

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Avatrombopag, an oral thrombopoietin receptor agonist: results of two double‐blind, dose‐rising, placebo‐controlled Phase 1 studies

Cited by 24 publications

References 13 publications

Updated international consensus report on the investigation and management of primary immune thrombocytopenia

Updated international consensus report on the investigation and management of primary immune thrombocytopenia

Current Advance in Thrombopoietin Receptor Agonists in the Management of Thrombocytopenia Associated With Chronic Liver Disease: Focus on Avatrombopag

Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease

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