Cabozantinib

Cabozantinib, sold under the brand-name Cabometyx and Cometriq, is a medication used to treat medullary thyroid cancer and a second line treatment for renal cell carcinoma among others. It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET. It was discovered and developed by Exelixis Inc.

Cabozantinib
Clinical data
Trade namesCabometyx, Cometriq, Cabozanix
Other namesXL184, BMS907351
License data
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding≥99.7%
    MetabolismHepatic (CYP3A4-mediated)
    Elimination half-life55 hours
    ExcretionFaeces (54%), urine (27%)
    Identifiers
    CAS Number
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.221.147
    Chemical and physical data
    FormulaC28H24FN3O5
    Molar mass501.514 g·mol−1
    3D model (JSmol)

    In 2012 cabozantinib in its capsule formulation was approved by the U.S. FDA under the name Cometriq for treating patients with medullary thyroid cancer.[1] The capsule form was approved in Europe for the same purpose in 2014.[2]

    In April 2016 the US FDA granted approval for marketing the tablet formulation as a second line treatment for kidney cancer[3] and the same was approved in Europe in October of that year.[4]

    Medical use

    Cabozantinib is used in two forms. A capsule form is used since 2012 to treat medullary thyroid cancer[5][6] and a tablet form is used since 2016 as a second line treatment for renal cell carcinoma.[7][8]

    Contraindications

    Cabozantinib has not been tested in pregnant women; it causes harm to fetuses in rodents. Pregnant women should not take this drug, and women should not become pregnant while taking it. It is not known if cabozantinib is excreted in breast milk.[6][8]

    The drug should be used with caution in people with a history of heart rhythm problems, including long QT interval.[8]

    Adverse effects

    In the US, the capsule formulation (Cometriq) carries a black box warning of the risk of holes forming in the stomach or intestines as well as formation of fistulas (tunnels between the GI tract and the skin). The black box also warns against the risk of uncontrolled bleeding.[5] The tablet formulation (Cabometyx) warns of these effects as well.[7][6][8]

    The labels also warn of the risk of clots forming and causing heart attacks or strokes, high blood pressure including hypertensive crisis, osteonecrosis of the jaw, severe diarrhea, skin sloughing off the palms and soles, a syndrome with headaches, confusion, loss of vision, and seizures, and protein appearing in urine.[5][7][6][8]

    Very common adverse effects (greater than 10% of people) include decreased appetite; low calcium, potassium, phosphate, and magnesium levels; high bilirubin levels; distorted sense of taste, headache, and dizziness; high blood pressure; distorted sense of hearing, earaches and sore throat; diarrhea, nausea, constipation, vomiting, stomach pain and upset stomach, and inflammation of the mouth and lips and a burning sensation in the mouth; skin sloughing off the palms and soles, hair color changes and hair loss, rash, dry skin, and red skin; joint pain and muscle spasms; fatigue and weakness; weight loss, elevated transaminases, higher cholesterol levels, and loss of red and white blood cells.[8]

    Common adverse effects (between 1% and 10% of people) include abscesses (inside the body, on the skin, and in teeth skin), pneumonia, inflamed hair follicles, fungal infections, low thyroid levels, dehydration, loss of albumin, anxiety, depression, and confusion, peripheral neuropathy, tingling, and tremor, tinnitus, atrial fibrillation, low blood pressure, blocked veins, paleness, chills, fistulas forming in the trachea and esophagus, blood clots in the lungs, and bleeding in the respiratory tract, GI perforation, bleeding in the stomach and intestines, pancreatitis, hemorrhoids, anal fissure, anal inflammation, gallstones, hard skin growths, acne, blisters, abnormal hair growth, loss of skin color and skin flaking, chest pain, blood or protein in urine, wounds that don't heal well, and facial swelling.[8]

    Interactions

    Grapefruit and grapefruit juice should be avoided as they may increase the concentration of the drug in the blood.[8]

    Cabozantinib is a substrate of CYP3A4 and multidrug resistance-associated protein 2; drugs that inhibit these enzymes will increase the half-life of cabozantinib and potentially increase its adverse effects; drugs that activate them may cause cabozantinib to be less effective.[8]

    It inhibits P-glycoprotein, so will change the availability of other drugs that depend on this transporter.[8]

    Pharmacology

    It inhibits the following receptor tyrosine kinases: MET (hepatocyte growth factor receptor protein) and VEGFR, RET, GAS6 receptor (AXL), KIT), and Fms-like tyrosine kinase-3 (FLT3).[8]

    History

    Cabozantinib (previously XL184) was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in January 2011.[9]

    Exelixis filed a new drug application with the FDA in the first half of 2012,[10] and on November 29, 2012 cabozantinib in its capsule formulation was granted marketing approval by the U.S. FDA under the name Cometriq for treating patients with medullary thyroid cancer.[1] The capsule form was approved in Europe for the same purpose in 2014.[2]

    In March 2016 Exelixis licensed to Ipsen worldwide rights (outside the US, Canada, and Japan) to market cabozantinib.[11]

    Exelixis' Phase III trial results of testing the drug in renal cancer published in the NEJM in 2015.[12] In April 2016 the FDA granted approval for marketing the tablet formulation as a second line treatment for kidney cancer[3] and the same was approved in Europe in October of that year.[4]

    Brand names

    In Bangladesh under the trade name Cabozanix.

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    See also

    References
    1. "Press release: FDA approves Cometriq to treat rare type of thyroid cancer". FDA. 29 November 2012. Archived from the original on July 7, 2014.
    2. "Cometriq Summary". EMA. Retrieved 8 August 2017.
    3. FDA Approval Announcement, April 2016
    4. "Cabometyx summary". EMA. Retrieved 8 August 2017.
    5. "Cabozantinib capsules (Cometriq) US label" (PDF). FDA. May 2016. For label updates see FDA index page for NDA 203756
    6. "Cabozantinib capsule (Cometriq) UK Summary of Product Characteristics (SPC) - (eMC)". UK Electronic Medicines Compendium. November 2016.
    7. "Cabozantinib tablets (Cabometyx) US label" (PDF). FDA. April 2016. For label updates see FDA index page for NDA 208692
    8. "Cabozantinib tablet (Cabometyx) UK Summary of Product Characteristics". UK Electronic Medicines Compendium. September 2016.
    9. Exelixis’ XL184 Granted Orphan Drug Designation and Assigned the Generic Name Cabozantinib. Jan 2011
    10. "Thyroid cancer drug cabozantinib prolongs PFS". Archived from the original on 2012-04-02. Retrieved 24 October 2011.
    11. Garde D (March 1, 2016). "Ipsen bets up to $855M on Exelixis' once-failed cancer drug". FierceBiotech.
    12. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. (November 2015). "Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma". The New England Journal of Medicine. 373 (19): 1814–23. doi:10.1056/nejmoa1510016. PMC 5024539. PMID 26406150.
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