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Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease.

ABSTRACT: Avatrombopag is an orally-administered small molecule thrombopoietin receptor agonist. It was the third thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and the first approved to treat periprocedural thrombocytopenia in patients with chronic liver disease (thereby providing an alternative to blood transfusions for these patients). Unlike eltrombopag, avatrombopag does not require a 4 hr food-restricted window around its use and it has not been associated with hepatotoxicity in ITP patients or portal vein thrombosis in patients with chronic liver disease. In ITP patients it can often be dosed less frequently than once daily. It is overall well-tolerated with a side-effect profile similar to placebo in randomized clinical trials. This article will review the clinical development, efficacy, safety, and pharmacology of avatrombopag for use in patients with ITP and thrombocytopenia of chronic liver disease.

SUBMITTER: Cheloff AZ

PROVIDER: S-EPMC6733339 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease.

Cheloff Abraham Z AZ Al-Samkari Hanny H

Journal of blood medicine 20190905

Avatrombopag is an orally-administered small molecule thrombopoietin receptor agonist. It was the third thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and the first approved to treat periprocedural thrombocytopenia in patients with chronic liver disease (thereby providing an alternative to blood transfusions for these patients). Unlike eltrombopag, avatrombopag does not require a 4 hr food-restricted window around its use and it has not been associated with ...[more]

PMID: 31565009

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Project description: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.

Project description:Chronic immune thrombocytopenia (ITP) is a debilitating autoimmune disorder that causes a reduction in blood platelets and increased risk of bleeding. ITP is currently managed with various pharmacologic therapies and splenectomy.This study was conducted to assess patient perceived and reported treatment side effects, as well as the perceived burden or bother, and need to reduce or stop treatment, associated with these side effects among adult patients with chronic ITP.A Web-enabled survey was administered to members of a US-based ITP patient support group. Patients reported demographic and clinical characteristics, ITP treatments' side effects for treatments received since diagnosed, level of bother (or distress), and need to reduce or stop treatment, associated with side effects. Current and past exposure was assessed for five specific treatment types: corticosteroids (CS), intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D), rituximab (RT), and splenectomy (SPL), as well as for other patient-referenced therapies (captured as "other").The survey was completed by 589 patients; 78% female, 89% white, mean age 48 years (SD = 14.71), and 68% reported a typical low platelet count of < 50,000/?L. Current or past treatment with CS was reported by 92% (n = 542) of patients, 56% (n = 322) for IVIg, 36% (n = 209) for anti-D, 36% (n = 213) for RT, and 39% (n = 227) for SPL. A substantial proportion of CS-treated patients reported side effects (98%, P < 0.05), were highly bothered by their side effects (53.1%, P < 0.05), and reported the need to stop or reduce treatment due to side effects (37.8%, P < 0.05). Among patients reporting side effects of treatment, significant associations were noted for the number of side effects, aggregate bother of reported side effects, and the need to stop or reduce treatment (all P < 0.05).Current ITP treatments, particularly corticosteroids, are associated with multiple bothersome side effects that may lead to patients stopping or reducing therapy. Open, informed and complete communication between clinician and patient regarding both the benefits and the side effects of ITP treatment may better prepare patients for their prescribed regimens.

Project description:IntroductionA network meta-analysis (NMA) was performed to assess the efficacy and safety of avatrombopag, relative to eltrombopag, romiplostim, and fostamatinib, for patients with chronic immune thrombocytopenia (ITP) not responding adequately to corticosteroids.MethodsA systematic search of publication and clinical trial databases was conducted to identify relevant randomized controlled trials (RCTs) and observational studies. Data from eligible studies were extracted and analyzed in a Bayesian framework using relative effect sizes vs placebo. Outcomes included durable platelet response; need for rescue therapy; reduction in use of concomitant ITP medication; incidence of any or World Health Organization (WHO) grade 2-4 bleeding events, and any adverse events. Results were reported as odds ratios or incidence rate ratios (IRR) with 95% credible intervals (CrIs).ResultsThe NMA included seven phase 3 RCTs. Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs eltrombopag (IRR 0.38 [95% CrI 0.19, 0.75]) and romiplostim (IRR 0.38 [95% Crl 0.17, 0.86]); no other between-treatment differences were observed.ConclusionIn this NMA, avatrombopag significantly increased the chance of achieving durable platelet response and reducing the use of concomitant ITP medication vs placebo, and significantly reduced the incidence of any bleeding events compared with placebo, eltrombopag, and romiplostim. The study aims to help guide clinicians managing patients with chronic ITP and insufficient response to previous treatment.

Project description:BackgroundAvatrombopag has been approved in patients who have severe thrombocytopenia (<50 × 109/L) and chronic liver disease (CLD) while receiving invasive procedures. The real-world application and effectiveness of avatrombopag in the subgroup patients with liver cancer remain unknown.MethodsLiver cancer patients (including primary liver cancer and colorectal cancer liver metastasis) who had severe thrombocytopenia and received avatrombopag were retrospectively enrolled. Avatrombopag dose, peak and absolute platelet count increase, combination treatment with other thrombopoietic agents, responder (peak count ≥50 × 109/L with absolute increase ≥20 × 109/L) rate, and anticancer treatment effect were analyzed. Thrombosis and bleeding events were assessed.ResultsIn total, 93 patients were enrolled, with 72 and 21 in the CLD and non-CLD groups, respectively. Patients with CLD had hepatitis B or C, larger spleen volume, and a higher cirrhosis degree. Baseline platelet counts were similar between two groups (median, 37.0 × 109/L vs. 39.0 × 109/L; P=0.594), while patients without CLD had higher peak platelet (median, 134.0 × 109/L vs. 74.0 × 109/L; P=0.015) and absolute increase (median, 101.0 × 109/L vs. 41.0 × 109/L; P=0.020) after avatrombopag treatment. The responder rate was higher in patients without CLD (100% vs. 76.4%; P=0.010). Combined avatrombopag with other thrombopoietic agents significantly increased platelet count; repeated use of avatrombopag produced similar effects with that of initial treatment. Concerning anticancer treatment effect, patients who responded to avatrombopag had a higher disease control rate. No thrombosis or hemorrhagic events were observed, even in patients with portal vein tumor thrombosis.ConclusionAvatrombopag was safe and effective and ensured successful implementation of anticancer treatment in liver cancer patients with severe thrombocytopenia, accompanied with or without CLD.

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Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease.

Publications

Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease.

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