What Is Avapritinib (Ayvakit)? FDA Approval, Licensing in Türkiye, and Reimbursement

• FDA-approved? Yes (first approved in 2020)
• Brand names: Ayvakit, BLU-285
• Active ingredient: Avapritinib
• Route of administration: By mouth (oral)
• Class: Signal transduction inhibitor, PDGFR-α and KIT inhibitor
• Category: Targeted therapy agent
• Manufacturer: Blueprint Medicines
• Distribution in Türkiye: Not yet licensed in Türkiye. It is obtained from abroad.
• Cancers for which it is approved:
  • Patients with unresectable or metastatic gastrointestinal stromal tumors (GIST), particularly those carrying PDGFRA exon 18 mutations or PDGFRA D842V mutations.
  • Advanced systemic mastocytosis.

What Is Ayvakit (Avapritinib)? How Does It Work?

Ayvakit, which contains the active ingredient avapritinib, is a signal transduction inhibitor that provides targeted therapy, particularly for patients with PDGFRA and KIT mutations. It acts in the treatment of cancers such as GIST and mastocytosis by stopping the growth and proliferation of tumor cells.

How Does It Work?

Avapritinib specifically targets activation-loop mutations in KIT and PDGFR-α (platelet-derived growth factor receptor-α). It also inhibits wild-type KIT, PDGFRA, PDGFRB, and CSFR1 proteins. This inhibitory effect suppresses cancer cell growth.

FDA Approval History

• 22 May 2023: The FDA approved Ayvakit (avapritinib) for indolent systemic mastocytosis (a slowly progressing mast cell disease). This became the first and only approved treatment for this disease.

• 16 June 2021: The FDA approved Ayvakit (avapritinib), developed by Blueprint Medicines, for treating adults with advanced systemic mastocytosis (a severe, rapidly progressing mast cell disease).

• 9 January 2020: The FDA approved Ayvakit (avapritinib) for treating patients with unresectable or metastatic gastrointestinal stromal tumors with PDGFRA exon 18 mutations (GIST).

Licensing in Türkiye

Ayvakit has not yet been licensed by the Republic of Türkiye Ministry of Health.

When its use is required, an application for off-label approval must be submitted to the Ministry. If approved, the drug may be obtained through the Turkish Pharmacists’ Association (TEB).

Is It Reimbursed?

Because it is not licensed in Türkiye, it is not considered within the Social Security Institution (SGK) reimbursement scheme.

Price: the cost of 1 month of treatment is approximately 41 thousand dollars in the United States and 30 thousand euros in Europe.

Resistance Mechanism

Resistance to treatment is associated with mutations in the KIT kinase domain (such as the T670I gatekeeper mutation) and alterations in PDGFRA exons 13, 14, and 15 (V658A, N659K, Y676C, and G680R mutations). By interfering with the drug’s mechanism of action, these mutations may cause tumors to develop resistance to treatment.

Absorption

Avapritinib is rapidly absorbed and reaches peak plasma levels 2-4 hours after oral administration. Steady drug levels are reached within 15 days. Fatty foods may increase absorption, leading to higher peak plasma concentrations and area under the curve (AUC).

Distribution

Avapritinib is 98.8% bound to plasma proteins, indicating extensive tissue distribution. A large proportion of the drug circulates in bound form, which is important for bioavailability.

Metabolism

Avapritinib is metabolized in the liver by CYP3A4 microsomal enzymes. One of its main metabolites is M690 (hydroxyglucuronide), and another is M499. Much of the drug is metabolized through oxidative deamination, with approximately 11% eliminated in feces and 18% in urine. Its half-life is approximately 57 hours.

Dose Range

The recommended dose for GIST and systemic mastocytosis is 300 mg, taken orally once daily. However, the dose may need to be reduced if systemic adverse effects occur.

Drug Interactions

1. Interaction 1: When used with CYP3A4 enzyme inhibitors such as ketoconazole, itraconazole, and erythromycin, avapritinib metabolism slows and the risk of toxicity increases.
2. Interaction 2: Phenytoin and other CYP3A4 enzyme inducers may reduce the drug’s effects.

Situations Requiring Caution

• Mild and Moderate Liver Impairment
  No reduction in the avapritinib dose is required for patients with mild to moderate liver impairment. However, because its effects in severe liver impairment have not been adequately studied, it must be used cautiously in this group. Closer monitoring for potential toxic effects is recommended.

• Kidney Impairment
  No dose adjustment is required for patients with mild to moderate kidney impairment. However, the safety and effectiveness of avapritinib have not been fully investigated in severe kidney impairment or end-stage kidney disease. It should therefore be administered cautiously to patients with severely impaired kidney function.

• Effects on the Central Nervous System (CNS)
  Avapritinib may have adverse effects on the central nervous system. These may include cognitive impairment (declining memory and thinking ability), dizziness, mood disturbances, sleep problems, speech disorders, and hallucinations. These effects may be more pronounced in older patients. If such symptoms develop during treatment, the drug may need to be stopped or its dose reduced.

• Changes in Mental Status and Bleeding Risk
  Sudden and severe changes in mental status may develop during avapritinib treatment. These are associated with the risk of intracranial bleeding (bleeding within the skull). Conditions such as subdural hematoma (blood collecting between the brain surface and skull) and cerebral hemorrhage have been observed. Because of the risk of brain bleeding, urgent medical help should be sought if patients develop symptoms such as headache, confusion, seizures, or loss of consciousness.

• Use with CYP3A Inhibitors
  Because avapritinib is largely metabolized by the CYP3A4 enzyme, using it with drugs that inhibit this enzyme (reduce its activity) may increase drug levels. This increases the severity of adverse effects and the risk of toxicity. If such a combination is unavoidable, the avapritinib dose must be reduced from 300 mg to 100 mg.

• Use with CYP3A Inducers
  Using avapritinib with CYP3A enzyme inducers (drugs that speed up this enzyme) may reduce its effectiveness. Such combinations are therefore not recommended. If their use is necessary, attention must be paid to dose adjustment and effectiveness.

• Use During Pregnancy and Breastfeeding
  Avapritinib has the potential to harm the fetus when used during pregnancy. Its use in pregnancy is strictly not recommended because of teratogenic effects (causing birth defects). Women of childbearing potential must use effective contraception during treatment and for at least 6 weeks after it ends. Women receiving avapritinib must also avoid breastfeeding during treatment and for at least 2 weeks afterward, because it is not known whether the drug passes into breast milk and it could potentially harm the infant.

• Use in Older Patients
  Adverse effects, particularly those involving cognitive function and mood, may be more common in older patients. Drug use should be monitored more carefully in this group. Dose adjustments and observation for adverse effects are important.

• Interactions with Other Drugs
  Avapritinib plasma levels may change when it is used with CYP3A4 inhibitors such as ketoconazole, itraconazole, and erythromycin, or CYP3A4 inducers such as phenytoin and rifampicin. Dose adjustment may be necessary. A physician must therefore review all drugs the patient takes concurrently.

Adverse Effects

The known adverse effects of Ayvakit, in order of frequency, are:

1. Fatigue, weakness, and loss of appetite
2. Cognitive impairment, dizziness, sleep disturbances, and hallucinations
3. Nausea, vomiting, diarrhea, and abdominal pain
4. Anemia and neutropenia
5. Intracranial bleeding
6. Periorbital edema and fluid retention
7. Changes in hair color