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Regorafenib

January 01, 1970

Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types.[2] By 2015 it had two US approvals for advanced cancers.

Regorafenib
Clinical data
Trade namesStivarga, Regonix
Other namesBAY 73-4506
AHFS/Drugs.comMonograph
MedlinePlusa613004
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability69-83%
Protein binding99.5%
MetabolismHepatic (UGT1A9-mediated)
Elimination half-life20-30 hours
ExcretionFeces (71%), urine (19%)
Identifiers
  • 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate
CAS Number
  • 755037-03-7
PubChem CID
  • 11167602
DrugBank
  • DB08896
ChemSpider
  • 9342697
UNII
  • 24T2A1DOYB
KEGG
  • D10138
ChEBI
  • CHEBI:68647 Y
ChEMBL
  • ChEMBL1946170
CompTox Dashboard (EPA)
  • DTXSID60226441
ECHA InfoCard100.248.939
Chemical and physical data
FormulaC21H15ClF4N4O3
Molar mass482.82 g·mol−1
3D model (JSmol)
  • Interactive image
  • CNC(=O)c1cc(ccn1)Oc2ccc(c(c2)F)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl
  • 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

Approvals and indications edit

Metastatic colorectal cancer edit

Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer[3] and has been approved by the US FDA on September 27, 2012.[4]

After a manufacturer's appeal Regorafenib was restored to the list of treatments funded by the English Cancer Drugs Fund.[5]

Advanced gastrointestinal stromal tumours edit

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.[6]

Advanced hepatocellular carcinoma edit

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.[7]

Clinical trials edit

MetastaticCRC: After the CORRECT trial, two phase 3 trials (CONSIGN, CONCUR) showed benefits compared to placebo. Regorafenib dosing was 150 or 160 mg/d for first 3 weeks of each 4 week cycle.[8]

Adverse effects edit

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).[9]

Other actions edit

Regorafenib and at least one of its analogs, sorafenib, are potent inhibitors of Soluble epoxide hydrolase (sEH).[10] 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.[10] 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,[10][11] 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.[12] 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.

Brand names edit

In Bangladesh under the trade name Regonix.[medical citation needed], Regora 40mg Tablet manufactured by Beacon Pharmaceuticals Ltd.

References edit

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ "Bayer Announces New Data on Oncology Portfolio To Be Presented at the ECCO-ESMO Congress 2009". Retrieved 2009-09-19.
  3. ^ . Archived from the original on 2012-01-19. Retrieved 2011-10-26.
  4. ^ "FDA approves new treatment for advanced colorectal cancer". 27 Sep 2012.
  5. ^ "Cancer fund reprieve for just one drug, Regorafenib". BBC. 22 May 2015. Retrieved 7 June 2015.
  6. ^ "FDA approves Stivarga for advanced gastrointestinal stromal tumors". 25 Feb 2013.
  7. ^ "Life extending treatment for patients with advanced liver cancer recommended by NICE". November 29, 2018.
  8. ^ CONSIGN, CONCUR Confirm Efficacy of Regorafenib in mCRC. 2015
  9. ^ "FDA Prescribing Information" (PDF). 27 Sep 2012.
  10. ^ a b c 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.
  11. ^ 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.
  12. ^ 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.

External links edit

  • "Regorafenib". Drug Information Portal. U.S. National Library of Medicine.

January 01, 1970
regorafenib, sold, under, brand, name, stivarga, among, others, oral, multi, kinase, inhibitor, developed, bayer, which, targets, angiogenic, stromal, oncogenic, receptor, tyrosine, kinase, shows, anti, angiogenic, activity, dual, targeted, vegfr2, tie2, tyros. Regorafenib sold under the brand name Stivarga among others is an oral multi kinase inhibitor developed by Bayer which targets angiogenic stromal and oncogenic receptor tyrosine kinase RTK Regorafenib shows anti angiogenic activity due to its dual targeted VEGFR2 TIE2 tyrosine kinase inhibition Since 2009 it was studied as a potential treatment option in multiple tumor types 2 By 2015 it had two US approvals for advanced cancers RegorafenibClinical dataTrade namesStivarga RegonixOther namesBAY 73 4506AHFS Drugs comMonographMedlinePlusa613004License dataEU EMA by INN US DailyMed RegorafenibPregnancycategoryAU DRoutes ofadministrationBy mouthATC codeL01EX05 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US WARNING 1 Rx onlyPharmacokinetic dataBioavailability69 83 Protein binding99 5 MetabolismHepatic UGT1A9 mediated Elimination half life20 30 hoursExcretionFeces 71 urine 19 IdentifiersIUPAC name 4 4 4 Chloro 3 trifluoromethyl phenyl carbamoyl amino 3 fluorophenoxy N methylpyridine 2 carboxamide hydrateCAS Number755037 03 7PubChem CID11167602DrugBankDB08896ChemSpider9342697UNII24T2A1DOYBKEGGD10138ChEBICHEBI 68647 YChEMBLChEMBL1946170CompTox Dashboard EPA DTXSID60226441ECHA InfoCard100 248 939Chemical and physical dataFormulaC 21H 15Cl F 4N 4O 3Molar mass482 82 g mol 13D model JSmol Interactive imageSMILES CNC O c1cc ccn1 Oc2ccc c c2 F NC O Nc3ccc c c3 C F F F ClInChI 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 Contents 1 Approvals and indications 1 1 Metastatic colorectal cancer 1 2 Advanced gastrointestinal stromal tumours 1 3 Advanced hepatocellular carcinoma 2 Clinical trials 3 Adverse effects 4 Other actions 5 Brand names 6 References 7 External linksApprovals and indications editMetastatic colorectal cancer edit Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer 3 and has been approved by the US FDA on September 27 2012 4 After a manufacturer s appeal Regorafenib was restored to the list of treatments funded by the English Cancer Drugs Fund 5 Advanced gastrointestinal stromal tumours edit 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 6 Advanced hepatocellular carcinoma edit 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 7 Clinical trials editMetastaticCRC After the CORRECT trial two phase 3 trials CONSIGN CONCUR showed benefits compared to placebo Regorafenib dosing was 150 or 160 mg d for first 3 weeks of each 4 week cycle 8 Adverse effects editRegorafenib 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 9 Other actions editRegorafenib and at least one of its analogs sorafenib are potent inhibitors of Soluble epoxide hydrolase sEH 10 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 10 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 10 11 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 12 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 Brand names editIn Bangladesh under the trade name Regonix medical citation needed Regora 40mg Tablet manufactured by Beacon Pharmaceuticals Ltd References edit FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 Oct 2023 Bayer Announces New Data on Oncology Portfolio To Be Presented at the ECCO ESMO Congress 2009 Retrieved 2009 09 19 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 FDA approves new treatment for advanced colorectal cancer 27 Sep 2012 Cancer fund reprieve for just one drug Regorafenib BBC 22 May 2015 Retrieved 7 June 2015 FDA approves Stivarga for advanced gastrointestinal stromal tumors 25 Feb 2013 Life extending treatment for patients with advanced liver cancer recommended by NICE November 29 2018 CONSIGN CONCUR Confirm Efficacy of Regorafenib in mCRC 2015 FDA Prescribing Information PDF 27 Sep 2012 a b c 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 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 amp Medicinal Chemistry Letters 23 13 3732 7 doi 10 1016 j bmcl 2013 05 011 PMC 3744640 PMID 23726028 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 External links edit Regorafenib Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Regorafenib amp oldid 1190968935, wikipedia, wiki, book, books, library,

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