If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus.
Spleen tyrosine kinase inhibitor42
Immune thrombocytopenic purpura†
Fostamatinib disodium hexahydrate (fostamatinib) is a prodrug for tamatinib (R406).27,43 Fostamatinib was granted orphan drug status for idiopathic thrombocytopenia (ITP) in 2015 and for autoimmune hemolytic anemia in 2018.21 Its FDA approval for the treatment of thrombocytopenia in adult patients with chronic ITP who are refractory to other forms of treatment marks the first-in-class license for a spleen tyrosine kinase (SYK) inhibitor. SYK kinase is expressed in hematopoietic cells and its inhibition results in less activation of mast cells, macrophages, and neutrophils; less B cell receptor–mediated activation of B lymphocytes; less related inflammatory responses and tissue damage; and other cellular responses (including less proliferation, differentiation, and phagocytosis).27,68-70 Fostamatinib was approved for the treatment of thrombocytopenia in adult patients with chronic ITP who are refractory to other forms of treatment.
Tamatinib is formed from fostamatinib through hydrolysis catalyzed by intestinal alkaline phosphatases.27,70 In patients with ITP, tamatinib acts to reduce antibody-mediated destruction of platelets by inhibiting IgG Fc gamma-receptor (FcγR) signaling.27,68-70 Off-target results of SYK inhibition by tamatinib both gives rise to some serious unwanted effects and also makes fostamatinib a potential candidate for a variety of other immuno-deranged inflammatory diseases.27,68,70 Among these are autoimmune hemolytic anemia, chronic graft versus host disease, and ovarian cancer.27,68,71,72
Due to the off-target effects, patients receiving fostamatinib must be monitored throughout therapy for the development of gastrointestinal toxicity (mainly serious diarrhea), hypertension, hepatotoxicity (i.e., increased transaminase levels), and neutropenia.43 Off-target effects preclude exposure in children <18 years of age (due to potential negative bone growth impacts)71 and exclude its use during pregnancy or by breast-feeding mothers.27,43,70 U.S. approval of fostamatinib was granted on determination of the risk:benefit analysis tipping in favor of benefit among 163 ITP study patients with persistent disease, as well as accumulated safety data from well over 4000 additional patient exposures.72,73 The initial dose of fostamatinib is 100 mg orally twice daily for 4 weeks, increased to 150 mg twice daily, if needed to achieve platelet counts ≥50 × 109/L, and then maintained at the minimum dose necessary to achieve treatment goals.43 Fostamatinib should be discontinued if treatment goals are not achieved within the first 12 weeks of therapy.43 As described in the product labeling, serious unwanted reactions are managed with dose reductions, interruption of treatment, or discontinuation and therapy.43
Tamatinib has a half-life of ~15 hours.43 It is extensively metabolized through CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation.27,43 Excretion is mainly through feces.25,83 Drug-drug interactions are expected to occur with strong CYP3A4 inhibitors, inducers, and substrates as well as substrates of P-glycoprotein and breast cancer resistance protein (e.g., rosuvastatin).43 The chemical structure of fostamatinib disodium hexahydrate is shown in Figure P1-2.74
Chemical structure of fostamatinib disodium (PubChem CID: 24828759; IUPAC Name: disodium;[6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate).
Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals