In this article, we will discuss Fedratinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2V617F or FLT3ITD, fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5, and improved survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis.
Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis. The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, with values returning to near baseline at 24 hours. After daily administration of fedratinib, levels of inhibition at steady state PK were similar to the maximal inhibition reached after the first dose of 300 (0.75 times the recommended dose), 400 or 500 mg (1.25 times the recommended dose) of fedratinib.
The potential for QTc prolongation with fedratinib was evaluated in 31 patients with solid tumors. No large mean increase in the QTc interval (>20 ms) was detected with daily dosing of fedratinib 500 mg (1.25 times the recommended dose) for 14 days.