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General Description:

Avapritinib, identified by CAS number 1703793-34-3, is a notable compound with significant therapeutic applications. 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 . Avapritinib was granted FDA approval on 9 January 2020 and EMA approval on 24 September 2020.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Avapritinib undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Avapritinib are crucial for its therapeutic efficacy: A 300mg oral dose of avapritinib reaches a C_max of 813ng/mL with a T_max of 2.0-4.1h and an AUC of 15400h\*ng/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Avapritinib is an important consideration for its dosing schedule: The half life of avapritinib is 32-57h. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Avapritinib exhibits a strong affinity for binding with plasma proteins: Avapritinib is 98.8% protein bound in serum. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Avapritinib from the body primarily occurs through: Avapritinib is 70% eliminated in the feces with 11% as the unchanged drug and 18% eliminated in the urine with 0.23% as the unchanged drug. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Avapritinib is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution is 1200L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Avapritinib is a critical factor in determining its safe and effective dosage: The mean apparent oral clearance of avapritinib is 19.5L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Avapritinib exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Avapritinib functions by: Avapritinib has a negative modulating effect on the transporters ABCB1 and ABCG2, which mediate the multidrug resistance phenotype of some cancers. This modulation may be due to interactions of avapritinib with the drug binding pocket of these transporters. Negative modulation of these transporters, resensitizes cancerous cells to treatment with chemotherapeutic agents like . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Avapritinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Bile Salt Export Pump Inhibitors, BSEP/ABCB11 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Kinase Inhibitor, MATE 1 Inhibitors, MATE 2 Inhibitors, MATE 2-K Inhibitors, MATE inhibitors, P-glycoprotein inhibitors, Protein Kinase Inhibitors, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.