New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations

Abstract

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.

Treatment of severe thrombocytopenia associated with systemic lupus erythematosus in pregnancy with eltrombopag: A case report and literature review

“…SLE patients who produce TPO‐R are more likely to develop thrombocytopenia and have a higher chance of not responding to glucocorticoid and immunoglobulin therapy 32 . Eltrombopag is an oral TPO‐R agonist that interacts with the transmembrane domain (cMpl) of TPO‐R, it promotes the proliferation and differentiation of pluripotent hematopoietic stem cells and megakaryocyte progenitor cells; meanwhile, it participates in megakaryocyte survival and anti‐apoptosis, thus increasing platelet production 33 . Eltrombopag is relatively convenient, safe and effective, and has been used as a second‐line drug to treat primary ITP and is widely used for secondary thrombocytopenia, providing a new therapeutic approach for refractory thrombocytopenia patients secondary to autoimmune diseases 34,35 .…”

The Role of Oncology Pharmacists in optimizing patient care in Chronic Immune Thrombocytopenia

“…The thrombopoietin receptor agonistbind and activate the thrombopoietin receptor to increase platelet production [17]. Eltrombopag and avatrombopag are oral nonpeptide drugs, whereas romiplostim is a subcutaneous peptide mimetic agent.…”

“…Safety findings were consistent with the previous phase 2 studies, with the most common adverse effect being headaches. There are no black box warnings, but it may cause fatigue, bruising, and arthralgia [21].Avatrombopag should be taken with food because it is a CYP2C9 and CYP3A substrate patients should be routinely tested for drug-drug interactions [17]. When being used for chronic immune thrombocytopenia, it is important to dose-adjust according to the recommended dose titration.…”

“…In adults with immune thrombocytopenia, spleen tyrosine kinase signaling is associated with phagocytosis-based, antibody-mediated destruction of platelets. The primary metabolite of fostamatinib, R406, inhibits activation of Fc receptors and B-cell receptors, leading to decreased platelet destruction [17]. Fostamatinib is typically reserved for patients whose other therapies, such as splenectomy, rituximab, or thrombopoietin receptor agonist, have failed.…”

“…Rituximab and cyclosporine might be better options in these patients while considering adverse effects and the concurrent treatment of cancer [2]. Chemotherapy agents are known to cause thrombocytopenia; however, this is distinctly different from immune thrombocytopenia, and chemotherapy-induced thrombocytopenia is not recognized as drug-induced immune thrombocytopenia [17]. Drug-induced immune thrombocytopenia is treated by discontinuing the offending agent, whereas chemotherapy-induced thrombocytopenia is treated by reducing chemotherapy doses, adjusting chemotherapy frequency, discontinuing chemotherapy, or providing platelet transfusions [5,17].…”