Fruquintinib - A Comprehensive Review

Overview

Fruquintinib is an oral tyrosine kinase inhibitor that primarily targets the vascular endothelial growth factor receptor (VEGFR). It belongs to a family of anti-angiogenic medicines which prevent the formation of new blood vessels. This is especially important in cancer treatment since tumors require a blood flow to get nutrients and oxygen for growth and survival. Fruquintinib was approved by the Food and Drug Administration (FDA) on 8 November 2023.

Indications

The specific indications of Fruquintinib:

• Adults with metastatic colorectal cancer (mCRC) who have previously had chemotherapy based on Fluoropyrimidines, Oxaliplatin, and Irinotecan.

• Adults with RAS wild-type mCRC who had previously received Fluoropyrimidine, Oxaliplatin, Irinotecan-based chemotherapy, and anti-VEGF treatment.

• Adults with RAS wild-type and EGFR-mutated mCRC who have previously had Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy, anti-VEGF treatment, and anti-EGFR therapy are being treated.

Contraindications

The contraindications of Fruquintinib:

• Arterial Thromboembolism: Patients with clinically severe cardiovascular disease, uncontrolled hypertension, or thromboembolic events during the last six months were excluded from Fruquintinib investigations. The use of Fruquintinib in individuals with a recent history of thromboembolic events should be approached with caution.

• Pregnancy: According to animal studies and the drug's mechanism of action, Fruquintinib may cause fetal damage if given to pregnant women.

• Moderate to Severe Hypertension: Fruquintinib has the potential to cause hypertension, and the median period from the first dosage to the development of hypertension was 14 days. During Fruquintinib therapy, blood pressure should be checked frequently.

Dosage Forms and Available Strengths

• Fruquintinib capsules have two strengths: one and five milligrams.

• For the treatment of metastatic colorectal cancer, the recommended dosage is five mg (milligrams) orally once a day for the first 21 days of each 28-day cycle or until disease progression or unacceptable toxicity occurs.

Warnings and Precautions for Fruquintinib

Patients and healthcare practitioners should be aware of various dangers and precautions associated with Fruquintinib. These are some examples:

• Hypertension: Fruquintinib has the potential to produce high blood pressure (hypertension). Patients' blood pressure should be tested regularly and controlled during therapy. Patients should contact the healthcare practitioner if they have headaches, dizziness, or shortness of breath.

• Hepatotoxicity: Frucquintinib may cause liver damage. Patients should be watched for liver disease indications, such as yellowing of the skin or whites of the eyes, lack of appetite, nausea or vomiting, dark-colored (tea-colored) urine, bleeding or bruises, or discomfort in the right upper stomach area.

• Arterial Thromboembolism: Fruquintinib should be taken with care in individuals with a recent history of thromboembolic events. If arterial thromboembolism (obstruction of blood vessels due to a clot from a different site) occurs, Fruquintinib should be stopped.

• Pregnancy: According to animal studies and the drug's mechanism of action, Fruquintinib may cause fetal damage if given to pregnant women. Women of reproductive potential should utilize effective contraception throughout and for at least two weeks following the final dosage of Fruquintinib.

• Bleeding: Fruquintinib can cause significant bleeding, including stomach or intestinal hemorrhage. Patients should be constantly watched for symptoms of bleeding and should not be given Fruquintinib if they have severe bleeding issues.

• Infections: Fruquintinib may make people more susceptible to infections or worsen illnesses. Patients should avoid contact with someone with a contagious infection (such as chickenpox) and notify the healthcare practitioner if they acquire symptoms of infection.

For Patients

What Is the Clinical Condition?

Fruquintinib is a small chemical inhibitor of vascular endothelial growth factor receptors (VEGFRs) that inhibits angiogenesis, a vital biological mechanism that increases oxygen supply to malignancies. In clinical studies, the medication displayed a tolerable safety profile and a substantial increase in overall survival (OS) and progression-free survival (PFS) compared to placebo with best supportive care (BSC).

How Effective Is Fruquintinib?

In clinical studies for the treatment of metastatic colorectal cancer (mCRC) in adults, Fruquintinib revealed good effectiveness. When taken at a 5 mg once daily dosage in cycles of three weeks on and one week off, Fruquintinib demonstrated good effectiveness with a sufficient safety profile in a phase-Ib study. In clinical studies such as FRESCO-2 and FRESCO-3, Fruquintinib significantly improved overall survival (OS) and progression-free survival (PFS) compared to placebo plus best supportive care (BSC).

What Are the Benefits of Fruquintinib?

Fruquintinib is primarily used to treat metastatic colorectal cancer (mCRC), and its advantages are linked to its tyrosine kinase inhibitor mode of action. The following are the main applications and possible advantages of Fruquintinib:

• Metastatic Colorectal Cancer (mCRC): Patients with metastatic colorectal cancer who have already had conventional chemotherapy, such as Fluoropyrimidine, Oxaliplatin, and Irinotecan, are eligible for Fruquintinib.

• Angiogenesis Inhibition: Fruquintinib is a tyrosine kinase inhibitor that inhibits the VEGFR (vascular endothelial growth factor receptor). Frucquintinib inhibits angiogenesis, the creation of new blood vessels that feed nourishment to tumors, by blocking VEGFR. This anti-angiogenic action is designed to decrease cancer cell proliferation and spread.

• Prolonging Progression-Free Survival: The major purpose of utilizing Fruquintinib is to lengthen the time between progressions in patients with metastatic colorectal cancer. PFS is the amount of time that the disease does not deteriorate during and after therapy.

• Treatment Following Standard Therapies: When other standard chemotherapy alternatives have been exhausted or are no longer effective, Fruquintinib is frequently explored as a therapeutic option for mCRC. It might be employed as a last-resort treatment.

What Is the Dosage of Fruquintinib?

• For the treatment of metastatic colorectal cancer (mCRC), the recommended dose of Fruquintinib is 5 mg orally once daily for the first 21 days of each 28-day cycle or until disease progression or intolerable toxicity.

• The capsules come in two strengths: 1 milligram and 5 milligrams. The suggested dose is 5 milligrams per capsule, which should be taken whole with or without food.

• The amount of medicine a patient takes is determined by the drug's strength, and the medication's duration is determined by the medical issue for which it is being used.

• If a patient misses a dosage, they should take it as soon as possible, but if the next dose is approaching, they should omit the missed dose and resume the usual dosing plan.

What Are the Side Effects of Fruquintinib?

The medicine has a reasonable safety profile, with some common adverse effects and fewer but more severe side effects. The following are common adverse effects of Fruquintinib:

• Gum bleeding.

• Vision distortion.

• Cloudy urine.

• Constipation.

• Fatigue.

• Appetite suppression.

• Diarrhea.

• Hand-foot syndrome.

• Proteinuria (high levels of protein in urine).

• Dysphonia (disorders of voice).

The following are less common yet serious adverse effects of Fruquintinib:

• Blood pressure that is too high.

• Severe headache.

• Confusion.

• Severe stomach ache.

• Constipation.

• Fever.

• Nauseousness or vomiting.

• Yellow eyes or skin (jaundice).

• Urine is dark in color.

• Red or black tarry stools.

• Trouble breathing.

• Unusual fatigue or weakness.

What Are the Precautionary Measures to Be Followed While Taking Fruquintinib?

• Regular Doctor Visits: It is essential to visit the physician regularly to evaluate the development of the medicine and ensure that it is working properly.

• Blood and Urine Tests: The doctor may order blood and urine tests to check for side effects.

• Pregnancy and Breastfeeding: If either spouse uses Fruquintinib during conception or pregnancy, it may damage the unborn child; before using any medicine while nursing, it is critical to consider the potential advantages against the potential hazards.

• Allergies: Report any unexpected or adverse responses to this or other drugs to the doctor.

• Medicine Disposal: Dispose of any obsolete or unused medicine with the advice of the healthcare expert.

• Medication Interactions: Inform the doctor about all the prescription and nonprescription medications, over-the-counter (OTC) medications, and herbal or vitamin supplements.

• Storage: Keep the medicine in a tightly sealed container at room temperature, away from heat, moisture, and direct light. Keep it out of children's reach.

Dietary Considerations, Missed Dose, Overdose, Storage, Handling

• Dietary Guidelines: Fruquintinib can be administered with or without meals.

• Dose Omitted: If a dosage is missed, take it immediately. If the next dosage approaches, the missed dose should be omitted, and the following dose should be taken normally. If vomiting develops after taking the medication, do not take another dosage.

• Overdose: The supplied sources did not provide information on the particular strategy for the treatment of drug overdose. In the event of a suspected overdose, seek medical care immediately.

• Handling and Storage: Fruquintinib should be kept at room temperature (mention the temperature) in a closed container away from heat, moisture, and direct light. It should be maintained from freezing temperatures and out of reach of youngsters. A healthcare practitioner's advice should be to dispose of outdated or unnecessary medications.

For Doctors

Pharmacodynamics

The pharmacodynamics of Fruquintinib includes:

• Antitumor Activity: Fruquintinib inhibits tumor growth by selectively inhibiting VEGFR1-3.

• Angiogenesis Inhibition: Fruquintinib inhibits angiogenesis by targeting VEGFR-1, -2, and -3, a vital biological mechanism for boosting oxygen supply to tumors.

• Metabolism: Fruquintinib is largely removed by CYP450 and non-CYP450 metabolism (that is, Sulfation and Glucuronidation). The CYP450 enzymes involved in the metabolism of Fruquintinib are CYP3A and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19.

Chemical Taxonomy

Fruquintinib is a chemical molecule with a unique chemical structure that belongs to the tyrosine kinase inhibitor class. It belongs to the chemical class known as small-molecule medicines. Here is a quick rundown:

• Classification of Chemicals: Fruquintinib is a tiny chemical in the class of organic compounds. It contains a complicated chemical structure that includes carbon, hydrogen, nitrogen, and oxygen components.

• Tyrosine Kinase Inhibitor (TKI): Fruquintinib is a tyrosine kinase inhibitor. Tyrosine kinases are enzymes that regulate cell development and signaling. By blocking these kinases, Frucquintinib disrupts the signaling pathways that lead to cancer cell proliferation.

• Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR): Fruquintinib primarily targets the tyrosine kinase vascular endothelial growth factor receptor (VEGFR). The suppression of VEGFR is designed to impair angiogenesis, a critical mechanism for tumor development.

• Pharmacological Classification: Pharmacologically, Fruquintinib is classed as an anti-angiogenic drug. Its principal method of action is angiogenesis inhibition via VEGFR targeting.

Mechanism of Action

Fruquintinib works therapeutically as a tyrosine kinase inhibitor, primarily targeting the vascular endothelial growth factor receptor (VEGFR). Here is a summary of its mode of action:

• Inhibition of Tyrosine Kinase: Fruquintinib is a tyrosine kinase inhibitor (TKI). Tyrosine kinases are enzymes in cell signaling pathways that control cell development and angiogenesis (the production of new blood vessels).

• VEGF Pathway Blockage: VEGF (vascular endothelial growth factor) is a signaling molecule essential for angiogenesis. Tumors frequently encourage angiogenesis to promote the creation of blood vessels, assuring a blood supply for growth.

• VEGFR Inhibition: Fruquintinib selectively inhibits VEGFR, a VEGF receptor. VEGFR is found on the surface of endothelial cells (cells that line blood arteries) and is essential for signaling that promotes angiogenesis.

• Anti-Angiogenic Properties: By inhibiting VEGFR, Fruquintinib disrupts the VEGF signaling pathway, decreasing angiogenesis. This anti-angiogenic action is designed to decrease tumor development by inhibiting the production of new blood vessels that give nutrition and oxygen to the tumor.

• Cancer Growth Suppression: Angiogenesis inhibition is an important technique in cancer treatment because it targets a mechanism essential for tumor development and metastasis. Fruquintinib works to decrease tumor proliferation by interrupting the blood supply.

• Treatment for Metastatic Colorectal Cancer (mCRC): Fruquintinib is predominantly used as a second-line medication in the treatment of metastatic colorectal cancer (mCRC), typically after other conventional chemotherapy alternatives have been tried.

Pharmacokinetics

The pharmacokinetics of Fruquintinib are as follows:

• Absorption: Fruquintinib is normally taken orally in the form of pills. The medicine is absorbed from the gastrointestinal system and enters the circulation area after oral intake.

• Distribution: Frucquintinib is spread throughout the body via circulation when it is ingested. The medication has the potential to infiltrate a variety of tissues, including the tumor location as well as normal tissues.

• Metabolism: Fruquintinib is broken down in the liver.

• Enzymes of Cytochrome P450: Some medications, such as tyrosine kinase inhibitors, are processed in the liver by cytochrome P450 enzymes. Understanding the role of individual cytochrome P450 enzymes in medication interactions might help predict probable interactions.

• Elimination: Fruquintinib and its metabolites are largely eliminated by the feces and, to a lesser extent, through the urine. Pharmacokinetic studies may highlight particular routes and excretion rates.

• Half-life: A drug's half-life is the amount of time it takes for half of the substance to be removed from the body. This value indicates how long the medicine will be active. The half life of Fruquintinib is 42 hours.

Toxicity

Here are some potential toxicities of Fruquintinib:

• High Blood Pressure (Hypertension): Hypertension is a frequent adverse effect of Fruquintinib. During therapy, blood pressure should be checked regularly, and antihypertensive drugs may be administered if necessary.

• Hand-Foot Syndrome (HFS): Hand-foot syndrome is a cutaneous response characterized by redness, swelling, and soreness on the palms of the hands and soles of the feet. If this occurs, dose adjustments or pauses may be required.

• Gastrointestinal Perforations: With Fruquintinib, there is a risk of gastrointestinal perforation. Patients should be watched for signs and symptoms, and medication should be halted or terminated if perforation occurs.

• Proteinuria: Proteinuria, or excess protein in the urine, may be caused by Fruquintinib. Urine protein levels should be monitored.

• Complications of Wound Healing: A higher chance of wound healing problems exists. The medicine should be stopped at least 28 days before elective surgery, and wound healing events should be treated cautiously.

• Thyroid Insufficiency: Thyroid malfunction can develop, including hypothyroidism and hyperthyroidism. Thyroid function should be checked frequently throughout therapy.

Drug Interactions

Here are some things to think about when using Fruquintinib:

• Enzymes of Cytochrome P450: Fruquintinib is broken down in the liver, and part of the process includes cytochrome P450 enzymes. Drugs that promote or inhibit these enzymes may affect Fruquintinib metabolism. Specific cytochrome P450 enzyme inhibitors or inducers may affect drug levels differently.

• Inhibitors of CYP3A4 Inhibition: Cytochrome P450 3A4 (CYP3A4) is the enzyme that breaks down Fruquintinib. Concurrent use of powerful CYP3A4 inhibitors may enhance Fruquintinib exposure, thus increasing the risk of adverse effects.

• Inducers of CYP3A4: Strong CYP3A4 inducers may reduce Fruquintinib exposure, lowering its efficacy. It is typically advised to avoid simultaneous usage with powerful CYP3A4 inducers.

• Antiplatelet and Anticoagulant Agents: There is an increased risk of bleeding when taking Fruquintinib with anticoagulants or antiplatelet medicines. It is advised that bleeding parameters be closely monitored.

Use in Specific Populations

The use of Fruquintinib in select populations, such as pregnant women, nursing mothers, and people with certain medical disorders, must be done with caution. Here is an outline of how Fruquintinib is used in different populations:

• Pregnancy: When given to pregnant people, Fruquintinib may cause fetal damage. It is not typically advised to be used during pregnancy, and women of reproductive potential should utilize effective contraception during therapy and for some time following the last dosage. Healthcare professionals should be contacted if a pregnancy occurs.

• Breastfeeding: The excretion of Fruquintinib into human milk is unclear. Therefore, there is a danger to the breastfeeding child. Breastfeeding should be avoided throughout Fruquintinib treatment, and women should not breastfeed for a set period following the final dosage.

• Fertility: The effect of Fruquintinib on human fertility is unknown. Patients who want to get pregnant should talk to their doctor about reproductive options, and adequate contraception should be used throughout and after therapy.

• Impaired Hepatic Function: Because Fruquintinib is processed in the liver, people with hepatic impairment may have abnormal metabolism of medication. The prescription instructions for the medicine usually include suggestions for dosage changes or specific considerations in patients with hepatic impairment.

• Impairment of the Renal System: The effect of renal impairment on Fruquintinib pharmacokinetics may be evaluated, and dosage changes may be required in individuals with compromised renal function. The prescription information contains specific recommendations.

• The Population of the Elderly: Elderly people may be more vulnerable to certain adverse effects, or they may experience age-related changes in organ function, which may impact the pharmacokinetics of Fruquintinib. In this population, close monitoring and changes may be recommended.

• Pediatric Use: The safety and efficacy of Fruquintinib in pediatric patients have yet to be determined. The medication is frequently prescribed to patients with metastatic colorectal cancer.