Avapritinb: Dosage, Directions, Indications, and Side-Effects

Overview

Avapritinib is a drug used to treat advanced systemic mastocytosis and tumors caused by a particular rare mutation. It is especially indicated for adults with metastatic or unresectable gastrointestinal stromal tumors (GIST) that carry a mutation in exon 18 of the platelet-derived growth factor receptor alpha (PDGFRA). Kinase inhibitors include Avapritinib.

Avapritinib was given the go-ahead by the US Food and Drug Administration (FDA) in January 2020. Fast track, breakthrough treatment, and orphan drug designations were given to the Avapritinib application.

Based on the findings of the Phase I NAVIGATOR clinical study, which included 43 GIST patients with PDGFRA exon 18 mutations, including 38 patients with the PDGFRA D842V mutation, Avapritinib was authorized.

How Does Avapritinib Work?

Avapritinib functions by preventing the action of a kinase known as KIT (Receptor tyrokinese), which is frequently altered in certain cancer cells, such as those found in gastrointestinal stromal tumors (GISTs) and systemic mastocytosis (SM). Signals sent by mutated KIT encourage the development and survival of cancer cells. Avapritinib can inhibit these signals from being delivered by blocking KIT, which slows or prevents the proliferation of cancer cells and may cause tumors to shrink.

Avapritinib can inhibit KIT in addition to PDGFR (platelet-derived growth factor receptor alpha), a different kinase important in encouraging cell growth and survival. Avapritinib has been demonstrated to be particularly successful in GISTs with a particular mutation in the PDGFRA gene (known as the exon 18 mutation), leading to its approval by the US FDA for this use.

In general, Avapritinib is a targeted medication that has anti-tumor effects by precisely inhibiting the activity of certain kinases that are crucial for the development and survival of cancer cells.

Available Dose and Dosage Forms:

Two oral tablet dosages of Avapritinib are offered: 25 mg (milligrams) and 100 mg. Round and biconvex in form, the pills are film-coated. Avapritinib dose recommendations are based on the condition being treated and other elements, including the patient's weight and general health.

1. The suggested dosage is 300 mg administered orally once a day with or without meals for the treatment of PDGFRA exon 18 mutation-carrying gastrointestinal stromal tumors (GISTs) that are inoperable or metastatic and include PDGFRA D842V mutations.

2. 200 mg given orally once a day with or without meals is the recommended dose for treating advanced systemic mastocytosis (SM).

Dosage modifications may be required depending on how the patient responds to the medication and any adverse effects that develop. Patients should strictly adhere to their healthcare professionals' dose and administration guidelines.

Directions

A healthcare professional with experience with anticancer drugs should be consulted before using Avapritinib. The patient's medical condition, age, weight, and other factors may affect the recommended dose and dosing regimen.

Here are some general guidelines for Avapritinib administration:

1. Following a doctor's instructions, Avapritinib is typically given once daily, with or without meals.

2. The pill should not be chewed, crushed, or broken; it should be eaten whole with a glass of water.

3. Patients should only make Avapritinib dosage changes or discontinue it after talking to their doctor.

4. Patients should notify their healthcare practitioner as soon as possible if they suffer any negative effects while taking Avapritinib. Dose modifications or brief treatment pauses may occasionally be required to address adverse effects.

Warnings

Patients should be aware of the following significant cautions associated with Avapritinib:

1. Risk of Liver Issues: Avapritinib can damage the liver, sometimes fatally or life-threatening. Patients with symptoms including jaundice, stomach discomfort, nausea, vomiting, or exhaustion should contact their doctor.

2. Risk of Bleeding: Avapritinib may make bleeding more likely, which might result in severe hemorrhage (blood rupture). If patients suffer signs like unusual bleeding or bruising, black or tarry stools, or coughing up blood, they should contact their healthcare professional.

3. Risk of Heart Issues: Avapritinib can alter heart rhythm, occasionally significantly or even fatally. Patients at higher risk include those with a history of cardiac issues or those taking drugs that can alter heart rhythm. Patients who develop symptoms including lightheadedness, dizziness, fainting, or irregular heartbeat should immediately contact their healthcare physician.

4. Risk of Central Nervous System Effects: Avapritinib has a risk of central nervous system side effects, including disorientation, dizziness, and impaired vision. Patients should refrain from tasks that call for mental attentiveness until they are familiar with how the medicine affects them.

5. Risk of Fetal Damage: Avapritinib should not be taken during pregnancy since it can harm a growing fetus. Sexually active women should use reliable contraception.

For Patients

What Is a Gastrointestinal Stromal Tumor?

1. An intestinal tumor called a gastrointestinal stromal tumor (GIST) develops from small or large intestine or stomach cells. GISTs can also develop in the rectum or esophagus. However, these locations for GISTs are rare.

2. Interstitial cells of Cajal, which are specialized cells that assist in regulating the passage of food through the digestive tract, are the source of GISTs. Although GISTs are normally slow-growing tumors, they can develop into malignant (cancerous) tumors.

3. GISTs can cause symptoms such as gastrointestinal bleeding, nausea, vomiting, and stomach discomfort. Some GISTs, on the other hand, did not present any symptoms and were discovered by chance during imaging tests or other medical procedures.

4. Typically, a biopsy to collect a tissue sample for microscopic analysis is combined with imaging tests, such as CT (Computed tomography) or MRI (magnetic resonance imaging) scans, to diagnose GIST.

5. Surgery to remove the tumor is typically followed by adjuvant therapy using specific drugs like Imatinib or Avapritinib to treat GISTs. Systemic therapy using targeted drugs may be used to aid in slowing the growth of the tumor and relieving symptoms in situations when the tumor cannot be physically removed or has spread to other regions of the body.

Before Starting Avapritinib:

Patients should disclose to their doctor any existing medical issues before beginning Avapritinib, including:

1. Liver Problems: Avapritinib may harm the liver, and individuals with the disease may be more susceptible to consequences. Before beginning therapy, patients with a history of liver illness should let their doctor know.

2. Heart Issues: Patients with a history of heart illness or taking certain drugs that might influence heart rhythm may be at higher risk due to the possibility that Avapritinib can induce changes in heart rhythm. Before beginning therapy, patients should let their healthcare practitioner know.

3. Bleeding Disorders: Patients with a history of bleeding problems or who use blood-thinning drugs may have a higher risk of bleeding since Avapritinib can make bleeding more likely. Before beginning therapy, patients should let their healthcare practitioner know.

4. Pregnancy: Avapritinib should not be taken during pregnancy or nursing since it might damage a growing fetus. While using Avapritinib and for at least six weeks following the final dosage, women of reproductive potential should utilize an effective form of contraception. Women using Avapritinib should not breastfeed because it is unknown if this drug is excreted in human milk.

Patients should also inform their doctor if they are taking other drugs, dietary supplements, or herbal remedies since these might interact with Avapritinib and alter its safety and efficacy. Patients may need baseline examinations to evaluate their heart function, blood cell counts, and liver and kidney function before beginning therapy with Avapritinib. Any pre-existing conditions that can compromise the safety of Avapritinib treatment can be found using these tests.

When and Why to Use Avapritinib?

1. Certain gastrointestinal stromal tumors (GISTs) with the genetic mutation known as PDGFRA exon 18 mutation are treated with Avapritinib. Additionally, it is used to treat GISTs that have spread to other areas of the body or do not respond to previous therapies.

2. A protein called KIT, which is abundant in GIST cells and promotes their growth and division, is the mechanism through which Avapritinib exerts its antitumor effects. Avapritinib can inhibit the development of GIST cells by inhibiting KIT.

3. Usually, Avapritinib is ingested orally, with or without meals. The patient's condition and reaction to therapy will determine the dosage and length of the course of treatment. Patients should carefully follow their doctor's recommendations and take their medicine as directed.

4. Patients may need to take Avapritinib for months or even years, as it is commonly used for long-term therapy. Even if the patient feels good, it is crucial to continue taking Avapritinib as prescribed to achieve optimum results.

5. While using Avapritinib, patients should notify their doctor immediately if any new or worsening symptoms, such as stomach discomfort, nausea, vomiting, bleeding, or heart rhythm changes, occur. During Avapritinib therapy, it may also be important to routinely evaluate heart function, blood cell counts, and liver and kidney function.

How Effective Is Avapritinib?

1. Avapritinib showed a high response rate in the NAVIGATOR clinical study, which assessed the drug's effectiveness in patients with advanced GISTs who had KIT exon 17 mutations. 38 (88 percent) of the 43 patients who received Avapritinib experienced a partial response, defined as a tumor reduction of at least thirty percent. Additionally, patients had a median progression-free survival of twenty-four months, during which their condition did not worsen.

2. Avapritinib also had a high response rate in the VOYAGER clinical study, which examined the drug's effectiveness in patients with advanced GISTs who had PDGFRA exon eighteen mutations. A partial response was seen in 27 (63 percent) of the 43 patients who received Avapritinib, and the median progression-free survival was 22.1 months.

3. Overall, clinical trials using Avapritinib to treat advanced GISTs with KIT or PDGFRA mutations have yielded positive outcomes.

Side Effects:

Avapritinib can have negative effects on certain people, just like any medicine.

Avapritinib's most frequent side effects include:

1. Nausea.

2. Vomiting.

3. Diarrhea.

4. Fatigue.

5. Edema (swelling).

6. Low red blood cell count, or anemia.

7. Continent pain.

8. A diminished appetite.

9. Spasms of muscles.

10. Rash.

Avapritinib's less frequent but possibly harmful side effects include:

1. Liver issues include hepatitis (liver inflammation) or increased liver enzymes.

2. Heart issues such as arrhythmias or prolonged QT intervals

3. Various types of bleeding, such as internal bleeding or cerebral bleeding.

4. Pancreatitis (pancreatic inflammation).

5. High blood pressure, or hypertension.

6. A side effect that can happen when cancer cells are eliminated too quickly is tumor lysis syndrome.

How to Take Avapritinib?

1. Avapritinib is commonly given orally once a day, with or without meals. The health and medical history of each patient may affect the advised Avapritinib dosage. Patients should adhere to their doctor's advice on the dosage and timing of Avapritinib.

2. The pills containing Avapritinib should not be chewed, crushed, or broken before being taken.

3. Patients taking other drugs, dietary supplements, or herbal remedies should let their doctor know since certain drugs may interact with Avapritinib. Patients should also disclose to their doctor if they have ever experienced liver, heart, or blood issues or any other illnesses.

4. Avapritinib must be taken exactly as directed, and any adverse effects or modifications to the patient's condition should be reported to the healthcare professional. Additionally, patients should let their doctor know if they have any new or worsening symptoms such as stomach discomfort, nausea, vomiting, or diarrhea since these might be indications of more serious side effects that need medical treatment.

What Should Be Done If the Dose Is Missed?

If a patient misses an Avapritinib dosage, they should resume their usual dosing schedule and take the missed dose as soon as possible if it is more than 12 hours before the next planned dose. To make up for a missed dosage, patients should not take a double dose because doing so increases the chance of unwanted effects. A patient should speak with their healthcare practitioner for advice if they have missed many Avapritinib doses or need clarification about what to do.

How to Treat Overdose?

1. The patient should seek emergency medical assistance if they take too much Avapritinib. Increased bleeding risk, variations in heartbeat or rhythm, and other adverse drug effects can all be signs of an overdose.

2. Avapritinib overdose has no specific antidote. The most common kind of treatment for an overdose is supportive care, which includes keeping an eye on the patient's vital signs, giving them oxygen, and giving them intravenous fluids.

3. Depending on the overdose's severity, the medical professional could also think about giving patients drugs to manage their symptoms, such as antiarrhythmics for an irregular heartbeat or blood products for managing bleeding.

4. Avapritinib overdoses must be avoided by adhering to the dosage and time recommendations given by the healthcare professional.

How to Store Avapritinib?

1. Avapritinib should be kept in its original container at room temperature, between 68 and 77 Fahrenheit (20 and 25°C), with the lid securely fastened. Children and animals should not be allowed access to the container.

2. Avapritinib must be kept dry and out of direct sunlight, moisture, and heat. Avapritinib should not be kept in the kitchen or bathroom since the heat and moisture in such locations might hinder the medication's effectiveness.

3. Avapritinib should not be used if it has expired or the pills are broken or discolored. Do not dump any leftover medication down the drain or toilet.

For Doctors

Indications

1. Avapritinib is prescribed for the treatment of adult patients with platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations, including PDGFRA D842V mutations, and an unresectable or metastatic gastrointestinal stromal tumor (GIST).

2. Adult patients with advanced systemic mastocytosis (SM), including those with aggressive SM, SM with an accompanying hematologic neoplasm, and mast cell leukemia, should also be treated with Avapritinib.

Dosing:

1. For a gastrointestinal stromal tumor (GIST) that is inoperable or has spread; 300 mg is administered orally once a day, with or without meals, until the condition worsens or the side effects become intolerable.

2. For mast cell leukemia, associated hematologic neoplasms, and advanced systemic mastocytosis (SM); 200 mg is administered orally once a day, with or without meals, until disease progression or intolerable toxicity.

Pharmacology

Mechanism of Action

An enzyme called Avapritinib, a kinase inhibitor, specifically blocks the activity of certain enzymes involved in cell signaling pathways. Avapritinib specifically targets and inhibits the activity of the KIT and PDGFRA kinases, which are mutated and active in systemic mastocytosis (SM) and gastrointestinal stromal tumors (GISTs). Avapritinib reduces tumor size and improves clinical outcomes by blocking these kinases and obstructing the signals that promote the development and survival of cancer cells.

With little to no action against other kinases and strong selectivity for KIT and PDGFRA, Avapritinib minimizes the possibility of off-target consequences. A vital therapeutic alternative for individuals with GIST or SM harboring PDGFRA D842V mutations, Avapritinib has also demonstrated activity against this mutation, which is resistant to existing therapies.

Pharmacodynamics

Avapritinib is a selective kinase inhibitor that modifies the activity of cell transporters adversely to make them more susceptible to further chemotherapies. As it is used once daily, its duration of effect is long. The dangers of cerebral hemorrhage, CNS side effects, and embryo-fetal damage should be discussed with patients.

Absorption - A 300 mg oral dosage of Avapritinib produces an AUC of 15400h Nanograms per milliliter (ng/ml), a Cmax of 813ng/mL, and a Tmax of 2.0-4.1hour (H).

Dimensions of Dispersion - 1200 liters (L) is the average apparent volume of the distribution.

Involving Proteins - In serum, Avapritinib is 98.8 percent protein bound.

Metabolism - In vitro, CYP3A4 and CYP2C9 are principally responsible for Avapritinib metabolism. Recovery from a 310 mg oral dosage includes 49 percent unmodified drug, 35 percent hydroxyglucuronide metabolite, and 14 percent oxidatively deaminated metabolite.

Method of Exclusion - 70 percent of Avapritinib is removed in the feces, 11 percent of the medication remains intact, 18 percent is eliminated in the urine, and 0.23 percent remains unaltered.

Half-life - Avapritinib has a half-life of 32 to 57 hours.

Toxicity

Clinical toxicity:

1. Nausea.

2. Vomiting.

3. Diarrhea.

4. Continent pain.

5. Fatigue.

6. Borderline edema.

7. Anemia.

8. Neutropenia.

9. Elevated liver enzyme levels.

10. Spasms of muscles.

Non-clinical Toxicity:

1. Gastrointestinal mucosal ulceration and perforation occur more frequently in animal studies.

2. Large dosages of the drug cause male rats' reproductive problems.

3. High doses of developmental harm in pregnant animals.

Contraindications

1. Patients who have previously experienced a serious allergic reaction to Avapritinib or its components should not use Avapritinib.

2. Strong CYP3A inducers or inhibitors should not be provided alongside Avapritinib since they might change the drug's pharmacokinetics and raise the possibility of negative side effects. Before beginning Avapritinib treatment, patients should disclose any drugs, herbal remedies, or supplements they use to their healthcare practitioner.

3. As Avapritinib may damage the fetus or newborn, it is not advised for use in pregnant or nursing women. During therapy and for at least two weeks following the final dosage of Avapritinib, women with the potential to get pregnant should utilize an effective method of contraception.

4. Avapritinib should be used cautiously by patients with significant hepatic impairment since these patients may have altered Avapritinib pharmacokinetics. A dosage change is not necessary for patients with severe renal impairment.

Drug Interactions:

The following medicines may interact with Avapritinib:

1. Strong CYP3A Inhibitors: Co-administration of Avapritinib with potent CYP3A inhibitors, such as Ketoconazole, Clarithromycin, and Ritonavir, can enhance Avapritinib exposure and raise the risk of side effects. As a result, it is best to avoid using potent CYP3A inhibitors when taking Avapritinib.

2. Strong CYP3A Inducers: Avapritinib's exposure can be decreased when it is co-administered with strong CYP3A inducers such as Rifampin, Carbamazepine, and Phenytoin, which can result in diminished effectiveness. As a result, it is best to refrain from using potent CYP3A inducers when taking Avapritinib.

3. Anticoagulants: Combining Avapritinib with anticoagulants, including Warfarin, Heparin, and Aspirin, might make bleeding more likely. If using Avapritinib with anticoagulants, patients should be closely watched for any indications of bleeding.

4. P-glycoprotein (P-gp): Avapritinib is a substrate of the P-glycoprotein (P-gp), and co-administration with P-gp inhibitors or inducers may change Avapritinib's pharmacokinetics. Patients should let their doctor know if they take any drugs known as P-gp inducers or inhibitors.

Other Specifications:

Pregnancy: Avapritinib can potentially damage the fetus when given to a pregnant woman. It is categorized as category D for pregnancy. Effective contraception during Avapritinib therapy and for at least a week following the final dosage is advised for sexually active women. Avapritinib should not be used to become pregnant; patients should be made aware of this possibility. When used during pregnancy, Avapritinib should only be used if the benefits outweigh the risks to the developing fetus.

Breastfeeding: It is uncertain if Avapritinib is secreted in breast milk during nursing. Women should not breastfeed throughout Avapritinib treatment and for at least a week following the final dosage due to the possibility of major adverse effects in nursing newborns.

Patients Over 65: Avapritinib's safety and effectiveness in this population have not been demonstrated. However, there were no differences in safety or effectiveness in clinical trials between those under 65 and those younger. As a result, changing the Avapritinib dosage is unnecessary, depending only on the patient's age. Elderly people, however, may be more prone to negative side effects such as tiredness, anemia, and peripheral edema.