In this article, we will discuss Avapritinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V, PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC50s) less than 25 nM in biochemical assays. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors which can contribute to tumor and mast cell proliferation. Other potential targets for avapritinib include wild type KIT, PDGFRB, and CSFR1. In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V with an IC50 of 4 nM, approximately 48-fold lower concentration than wild-type KIT. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with KIT exon 17 mutation. Avapritinib inhibited the autophosphorylation of PDGFRA D842V, a mutation associated with resistance
to approved kinase inhibitors, with an IC50 of 30 nM. Avapritinib also had anti-tumor activity in mice implanted with an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/17 mutations.
Based on the data from four clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER, and PATHFINDER, higher exposure was
associated with increased risk of Grade ≥ 3 related adverse effects, any Grade pooled cognitive adverse effects, Grade ≥ 2 pooled cognitive adverse effects, and Grade ≥ 2 pooled edema adverse effects over the dose range of 30 mg to 400 mg (0.1 to 1.33 times the recommended dose for GIST and 0.15 to 2 times the recommended dose for AdvSM) once daily. Based on exposure and efficacy data from EXPLORER and PATHFINDER (n=84), higher avapritinib exposure was associated with faster time to response over the dose range of 30 mg to 400 mg (0.15 to 2 times the recommended dose for AdvSM) once daily.
The effect of Avapritinib on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered dose of 300 mg or 400 mg (1.33 times the recommended 300 mg dose) once daily. No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (Cmax) of 899 ng/mL.