akr-501 and Chronic-Disease

Avatrombopag (Doptelet

Topics: Adult; Animals; Chronic Disease; Humans; Liver Diseases; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Thrombocytopenia

Severe thrombocytopenia (platelet count < 50 x 109/l) is the most frequent hematological disorder in patients with chronic liver disease, affecting 64-84 % of individuals with cirrhosis. The pathophysiological mechanisms that underlie thrombocytopenia are complex, but the reduction of thrombopoietin levels is considered to play a key role. Until recently, there was a continuous debate about the optimal management of patients with chronic liver disease and whether low platelet counts require a scheduled invasive procedure. Transfusion of platelet concentrates is considered to be the standard treatment, but has major limitations such as its short lifespan, limited efficacy and relevant adverse effects. Avatrombopag is an oral thrombopoietin receptor agonist that induces megakaryocytic proliferation and differentiation and platelet production. It has been approved by the Spanish Agency of Medicines and Health Products for the treatment of severe thrombocytopenia in adult patients with chronic liver disease before scheduled procedures, to decrease the risk of bleeding. Randomized trials have demonstrated that this agent is effective in maintaining platelet counts above 50 × 109/l over a period of more than two weeks, with a similar safety profile to the placebo. In this article, we review avatrombopag in the treatment of thrombocytopenia in patients with chronic liver disease. Furthermore, the main differences of this intervention in comparison to the previous standard of care therapy are discussed.

Topics: Adult; Chronic Disease; Humans; Liver Diseases; Thiazoles; Thiophenes; Thrombocytopenia

Thrombocytopenia is common in advanced liver disease, and such patients frequently need invasive procedures. Numerous mechanisms for thrombocytopenia exist, including splenic sequestration and reduction of levels of the platelet growth factor thrombopoietin. Traditionally, platelet transfusions have been used to increase platelet counts before elective procedures, usually to a threshold of greater than or equal to 50,000/μL, but levels vary by provider, procedure, and specific patient. Recently, the thrombopoietin receptor agonists avatrombopag and lusutrombopag were studied and found efficacious for increasing platelet count in the outpatient setting for select patients with advanced liver disease who need a procedure.

Topics: Chronic Disease; Cinnamates; Hemorrhage; Humans; Liver Diseases; Platelet Count; Platelet Transfusion; Receptors, Thrombopoietin; Risk Factors; Surgical Procedures, Operative; Thiazoles; Thiophenes; Thrombocytopenia; Thrombopoiesis

Avatrombopag (Doptelet

Topics: Chronic Disease; Drug Approval; Humans; Liver Diseases; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Thrombocytopenia; United States; United States Food and Drug Administration

Avatrombopag maleate (Doptelet; Dova Pharmaceuticals) is an oral, small-molecule second-generation thrombopoietin (TPO) receptor agonist under development for the treatment of thrombocytopenia. Recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease on the basis of the results of two phase III trials, it is currently under investigation for treatment of immune thrombocytopenia (two randomized trials demonstrating efficacy have already been completed), chemotherapy-induced thrombocytopenia and perioperative thrombocytopenia in patients undergoing major surgical procedures. This review will evaluate the preclinical pharmacology, pharmacokinetics, clinical studies, safety, indications and drug interactions of avatrombopag, with a focus on its use for the treatment of periprocedural thrombocytopenia in patients with chronic liver disease.

Topics: Animals; Chronic Disease; Drug Interactions; Hematologic Agents; Humans; Liver Diseases; Perioperative Period; Thiazoles; Thiophenes; Thrombocytopenia; Treatment Outcome

Thrombocytopenia (platelet count <150 × 10(9)/L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6% among non-cirrhotic patients with chronic liver disease to 70% among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient's risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia.

Topics: Benzoates; Chronic Disease; Disease Management; Hepatitis C, Chronic; Humans; Hydrazines; Liver Diseases; Pyrazoles; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thiazoles; Thiophenes; Thrombocytopenia; Thrombopoietin

Essentials Thrombopoietin (TPO) lowers the threshold for platelet activation. TPO receptor agonists (RAs) may therefore also lead to platelet activation. Patients with chronic liver disease and thrombocytopenia participated in a randomized trial. The TPO-RA avatrombopag did not increase platelet activation in vivo or reactivity in vitro.. The thrombopoietin (TPO) receptor agonist (TPO-RA) avatrombopag has recently been Food and Drug Administration-approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) scheduled for a procedure. The TPO receptor c-mpl is expressed on the platelet surface, and TPO lowers the threshold for platelet activation. TPO-RAs may therefore also lead to platelet activation.. To evaluate the effects of avatrombopag on platelet activation.. CLD patients with thrombocytopenia participated in a randomized, double-blind, placebo-controlled, parallel-group study. No patient received a platelet transfusion within 10 days of study blood draws. Platelet activation was evaluated with whole blood flow cytometry (which, unlike other methods, is accurate in thrombocytopenic samples).. Avatrombopag, but not placebo, increased platelet counts. As measured by platelet surface P-selectin and activated glycoprotein IIb-IIIa: (i) the numbers of circulating activated platelets were not increased in avatrombopag-treated patients as compared with placebo-treated patients; and (ii) platelet reactivity to low and high concentrations of ADP and thrombin receptor-activating peptide was not increased in avatrombopag-treated patients as compared with placebo-treated patients.. In this randomized, double-blind, placebo-controlled, parallel-group study of CLD patients with thrombocytopenia, avatrombopag increased platelet counts but did not increase platelet activation in vivo or platelet reactivity in vitro.

Topics: Blood Platelets; Chronic Disease; Double-Blind Method; Hematologic Agents; Humans; Liver Diseases; Platelet Activation; Platelet Count; Thiazoles; Thiophenes; Thrombocytopenia; Thrombopoiesis; Time Factors; Treatment Outcome; United States

Stimulation of platelet production by thrombopoietin-receptor agonists (TPO-RAs) is an effective second-line treatment in immune thrombocytopenia (ITP). This 28-day phase 2 study assigned subjects with ITP of ≥3 months to once-daily oral avatrombopag (2.5, 5, 10, or 20 mg), an investigational nonpeptide TPO-RA active in humans, or placebo; subjects completing randomized treatment could enroll in a 24-week extension study. Of 64 randomized subjects, 13% (avatrombopag 2.5 mg), 53% (5 mg), 50% (10 mg), and 80% (20 mg), vs 0% for placebo, achieved a platelet count (PC) response of ≥50 × 10(9)/L with ≥20 × 10(9)/L increase above baseline at day 28. Fifty-three subjects (83%) entered the extension: 52% and 76% had a durable (PC response at ≥75% of their platelet assessments over the last 14 weeks) and overall (stable response or response at any ≥2 consecutive visits) response, respectively. All subjects experienced ≥1 adverse event (AE) (most commonly fatigue, headache, and epistaxis); 19% (n = 12) reported ≥1 serious AE; 10 (16%) withdrew due to an AE (5 due to increased PC). Avatrombopag was active and generally well tolerated, with PC response rates and AE incidence comparable with other TPO-RAs. These studies were registered at www.clinicaltrials.gov as #NCT00441090 and #NCT00625443.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drugs, Investigational; Epistaxis; Fatigue; Female; Headache; Humans; Male; Middle Aged; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Time Factors; Treatment Outcome