Avapritinib

Absorption

A 300mg oral dose of avapritinib reaches a Cmax of 813ng/mL with a Tmax of 2.0-4.1h and an AUC of 15400h*ng/mL.

Toxicity

Data regarding overdoses of avapritinib are not readily available.

Description

BLU-285 is a dual inhibitor of KIT receptor and platelet-derived growth factor receptor α (PDGFRα) tyrosine kinases with activating loop mutations (IC₅₀s = 0.27 and 0.24 nM for KIT^D816V and PDGFRα^D842V, respectively). It is >150-fold selective for KIT^D816V and PDGFRα^D842V over a kinase panel at a concentration of 3 μM. BLU-285 also has activity against a panel of KIT and PDGFRα loop mutants identified in patients with gastrointestinal stromal tumors (GISTs; IC₅₀s = <100 nM). It inhibits growth of cancer cell lines containing wild-type and mutant KIT and PDGFRα, demonstrating increased potency in cell lines expressing KIT and PDGFRα with activating loop mutations. BLU-285 (0.3-30 mg/kg) reduces tumor volume in a P815 KIT^D814Y mastocytoma allograft mouse model and a GIST patient-derived mouse xenograft model in a dose-dependent manner. Formulations containing BLU-285 have been used to treat KIT- and PDGFRα-driven malignancies.

The Uses of Avapritinib

Avapritinib is a medication used for the treatment of tumors due to one specific rare mutation. Avapritinib is a potent, selective, and orally active KIT and PDGFRA activation loop mutant kinases inhibitor.

Indications

Avapritinib is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.
It is also used to treat adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia. However, it is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 109 L.

Background

Avapritinib, or BLU-285, is a selective tyrosine kinase inhibitor of KIT and platelet derived growth factor receptor alpha indicated for the treatment of unresectable, metastatic gastrointestinal stromal tumors and advanced systemic mastocytosis. It is one of the first medications available for the treatment of multidrug resistant cancers. Avapritinib shares a similar mechanism with ripretinib.
Avapritinib was granted FDA approval on 9 January 2020 and EMA approval on 24 September 2020.

Indications

Avapritinib is approved for the treatment of adult patients with unresectable or metastatic gastrointestinal mesenchymal stromal tumour (GIST) carrying platelet-derived growth factor receptor A (PDGFRA) exon 18 mutations, including the D842V mutation, as well as adult patients with advanced systemic mastocytosis (ASM).

brand name

Ayvakit

General Description

Class: receptor tyrosine kinase; Treatment: GIST, SM; Other name: BLU-285; Elimination half-life = 32–57 h; Protein binding = 98.8%

Pharmacokinetics

Avapritinib is a selective kinase inhibitor that negatively modulates the action of cell transporters to resensitize them to other chemotherapies. It has a long duration of action as it is given once daily. Patients should be counselled regarding the risk of intracranial hemorrhage, CNS effects, and embryo-fetal toxicity.

Metabolism

Avapritinib is metabolized mainly by CYP3A4 and CYP2C9 in vitro. A 310mg oral dose is recovered as 49% unchanged drug, 35% hydroxy glucuronide metabolite, and 14% oxidatively deaminated metabolite.