Regorafenib

Regorafenib
Names
Trade namesStivarga, Regonix
Other namesBAY 73-4506
IUPAC name
  • 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate
Clinical data
Drug classProtein kinase inhibitor[1]
Main usesColorectal cancer, gastrointestinal stromal tumors (GIST), hepatocellular cancer[2]
Side effectsPain, tiredness, rash, diarrhea, infection, high blood pressure[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    use    		By mouth
    Typical dose160 mg OD[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa613004
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability69-83%
    Protein binding99.5%
    MetabolismHepatic (UGT1A9-mediated)
    Elimination half-life20-30 hours
    ExcretionFeces (71%), urine (19%)
    Chemical and physical data
    FormulaC21H15ClF4N4O3
    Molar mass482.82 g·mol−1
    3D model (JSmol)
    SMILES
    • CNC(=O)c1cc(ccn1)Oc2ccc(c(c2)F)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl
    InChI
    • InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
    • Key:FNHKPVJBJVTLMP-UHFFFAOYSA-N

    Regorafenib, sold under the brand name Stivarga among others, is a medication used to treat colorectal cancer, gastrointestinal stromal tumors (GIST), and hepatocellular cancer.[2] It is used after other treatments have failed.[2] It is taken by mouth.[2]

    Common side effects include pain, tiredness, rash, diarrhea, infection, and high blood pressure.[1] Other side effects may include liver problems, bleeding, and gastrointestinal perforation.[1] It is a protein kinase inhibitor including the VEGF receptors and FGF receptors.[1][2]

    Regorafenib was approved for medical use in the United States in 2012 and Europe in 2013.[2][1] In the United Kingdom 4 weeks of treatment costs the NHS about £3,750 as of 2021.[3] In the United States this amount costs about 19,600 USD.[4]

    Medical uses

    Colorectal cancer

    Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer[5] and has been approved by the US FDA on September 27, 2012.[6]

    After a manufacturer's appeal Regorafenib was restored to the list of treatments funded by the English Cancer Drugs Fund.[7]

    Gastrointestinal stromal tumours

    On February 25, 2013 the US FDA expanded the approved use to treat patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other FDA-approved treatments for this disease. In a clinical study with 199 patients regorafenib treated patients had a delay in tumor growth (progression-free survival) that was, on average, 3.9 months longer than patients who were given placebo.[8]

    Hepatocellular carcinoma

    On November 29, 2018 the National Institute for Health and Care Excellence (NICE) approved use of regorafenib in patients with advanced hepatocellular carcinoma who were previously treated with sorafenib.[9]

    Dosage

    It is taken for 21 days out of 28 days at a dose of 160 mg per day.[3]

    Side effects

    Regorafenib is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with regorafenib during clinical studies. Serious side effects, which occurred in less than one percent of patients, were liver damage, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks and perforations (holes) in the intestines. The most common side effects reported in patients treated with regorafenib include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhoea, mouth sores (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).[10]

    Mechanism of action

    Regorafenib and at least one of its analogs, sorafenib, are potent inhibitors of Soluble epoxide hydrolase (sEH).[11] sEH metabolizes, and in general thereby inactivates, epoxyeicosatrienoic acids (EETs), epoxydocosapentaenoic acids (EDPs), epoxyeicosatetraenoic acids (EEQs), and other epoxy polyunsaturated fatty acids that are made by various cytochrome P450 epoxygenases. EETs, EDPs, and EEQs have various effects in animals including vasodilation, anti-hypertensive, and anti-blood-clotting actions. However, EDPs, unlike EETs, inhibit the vascularization, growth, and metastasis of human cancer cells in vitro and in animal models.[11] It is suggested that the inhibition of sEH and consequential increase in EDP levels contributes to the anti-cancer activity of regorafenib and related analogs,[11][12] a possibility supported by studies showing that 1) DHA acted synergistically with regorafenib to increase EDP levels in and inhibit the growth of several human renal cancer cell lines in vitro and 2) dietary DHA likewise acted synergistically with regorafenib to inhibit the invasiveness and growth of a human renal cancer cell line while increasing its EPA levels in mice.[13] These preclinical studies suggest that dietary supplementation with omega-3 fatty acids, particularly DHA, may be useful in enhancing the anti-cancer actions of regorafenib in humans.

    Society and culture

    Brand names

    In Bangladesh under the trade name Regonix., Regora 40mg Tablet manufactured by Beacon Pharmaceuticals Ltd.

    References

    1. 1 2 3 4 5 6 "Stivarga". Archived from the original on 6 March 2021. Retrieved 16 October 2021.
    2. 1 2 3 4 5 6 "Regorafenib Monograph for Professionals". Drugs.com. Archived from the original on 20 September 2020. Retrieved 16 October 2021.
    3. 1 2 3 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1053. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    4. ↑ "Stivarga Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 6 March 2016. Retrieved 16 October 2021.
    5. ↑ "Phase III Trial of Regorafenib in Metastatic Colorectal Cancer Meets Primary Endpoint of Improving Overall Survival". Archived from the original on 2012-01-19. Retrieved 2011-10-26.
    6. ↑ "FDA approves new treatment for advanced colorectal cancer". 27 Sep 2012. Archived from the original on 18 January 2017. Retrieved 6 January 2021.
    7. ↑ "Cancer fund reprieve for just one drug, Regorafenib". BBC. 22 May 2015. Archived from the original on 26 May 2015. Retrieved 7 June 2015.
    8. ↑ "FDA approves Stivarga for advanced gastrointestinal stromal tumors". 25 Feb 2013. Archived from the original on 18 January 2017. Retrieved 6 January 2021.
    9. ↑ "Life extending treatment for patients with advanced liver cancer recommended by NICE". November 29, 2018. Archived from the original on November 29, 2018. Retrieved January 6, 2021.
    10. ↑ "FDA Prescribing Information" (PDF). 27 Sep 2012. Archived (PDF) from the original on 2 December 2020. Retrieved 6 January 2021.
    11. 1 2 3 Zhang G, Kodani S, Hammock BD (January 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–23. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640.
    12. ↑ Hwang SH, Wecksler AT, Zhang G, Morisseau C, Nguyen LV, Fu SH, Hammock BD (July 2013). "Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors". Bioorganic & Medicinal Chemistry Letters. 23 (13): 3732–7. doi:10.1016/j.bmcl.2013.05.011. PMC 3744640. PMID 23726028.
    13. ↑ Kim J, Ulu A, Wan D, Yang J, Hammock BD, Weiss RH (May 2016). "Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy". Molecular Cancer Therapeutics. 15 (5): 890–8. doi:10.1158/1535-7163.MCT-15-0847. PMC 4873345. PMID 26921392.
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