| 词条 | Sorafenib |
| 释义 |
| verifiedrevid = 464405524 | IUPAC_name = 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide | image = Sorafenib2DACS.svg | width = 300 | image2 = Sorafenib3Dan.gif | width2 = 250 | tradename = Nexavar | Drugs.com = {{drugs.com|monograph|nexavar}} | MedlinePlus = a607051 | licence_EU = yes | licence_US = Sorafenib | pregnancy_AU = D | pregnancy_US = D | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = Oral | bioavailability = 38–49% | protein_bound = 99.5% | metabolism = Hepatic oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated) | elimination_half-life = 25–48 hours | excretion = Faeces (77%) and urine (19%) | IUPHAR_ligand = 5711 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 284461-73-0 | ATC_prefix = L01 | ATC_suffix = XE05 | PubChem = 216239 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00398 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 187440 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 9ZOQ3TZI87 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08524 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 50924 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1336 | PDB_ligand = BAX | C=21 | H=16 | Cl=1 | F=3 | N=4 | O=3 | molecular_weight = 464.825 g/mol | smiles = CNC(=O)c1cc(ccn1)Oc2ccc(cc2)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = MLDQJTXFUGDVEO-UHFFFAOYSA-N | synonyms = Nexavar Sorafenib tosylate }} Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),[1] is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma. Mechanism of actionSorafenib is a small inhibitor of several tyrosine protein kinases, such as VEGFR, PDGFR and Raf family kinases (more avidly C-Raf than B-Raf).[2][3][4] (See BRAF (gene)#Sorafenib for details of drug structure interaction with B-Raf.) Sorafenib treatment induces autophagy,[4] which may suppress tumor growth. However, autophagy can also cause drug resistance.[5] Medical usesAt the current time sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.[6][7][8][9] Kidney cancerClinical trial results, published January 2007, showed that, compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01).[10] In Australia this is one of two TGA-labelled indications for sorafenib, although it is not listed on the Pharmaceutical Benefits Scheme for this indication.[9][13] Liver cancerAt ASCO 2007, results from the SHARP trial[11] were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements; however, there was no significant difference in median time to symptomatic progression (p=0.77). There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis.[11] Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.[4] In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median time to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.[12] A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC)concluding that the combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.[13] In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib.[14] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.[9] Thyroid cancerOn November 22, 2013, sorafenib was approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.[15] The Phase 3 DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.[16] Desmoid tumorsA phase 3 clinical trial is under way testing the effectiveness of Sorafenib to treat desmoid tumors (also known as aggressive fibromatosis), after positive results in the first two trial stages. Dosage is typically half of that applied for malignant cancers (400 mg vs 800 mg). NCI are sponsoring this trial.[17][18] Adverse effectsAdverse effects by frequencyNote: Potentially serious side effects are in bold. Very common (>10% frequency) {{div col|colwidth=18em}}
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HistoryRenal cancerSorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,[61] and received European Commission marketing authorization in July 2006,[62] both for use in the treatment of advanced renal cancer. Liver cancerThe European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007,[63] and FDA approval for this indication followed in November 2007.[64] In November 2009, the UK's National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month.[65] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.[65] In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic Sorafenib, bringing its price down by 97%. Bayer sells a month's supply, 120 tablets, of Nexavar for{{INRConvert|280000}}. Natco Pharma will sell 120 tablets for {{INRConvert|8800}}, while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer.[66][67][68] Under Indian Patents Act, 2005 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.[69] ResearchLungIn some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.[70] Ovarian CancerSorafenib has been studied as maintenance therapy after ovarian cancer treatment and in combination with chemotherapy for recurrent ovarian cancer but did not show results that led to approval of the drug for these indications.[71] Brain (recurrent glioblastoma)There is a phase I/II study at the Mayo Clinic[72] of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma. Desmoid tumor (aggressive fibromatosis)A study performed in 2011 showed that Sorafenib is active against aggressive fibromatosis. This study is being used as justification for using Sorafenib as an initial course of treatment in some patients with aggressive fibromatosis.[73] Nexavar controversyIn January 2014, Bayer's CEO stated that Nexavar was developed for "Western Patients Who Can Afford it, NOT for Poor Indians". At the exceedingly generous prices, a kidney cancer patient would pay $96,000 (£58,000) for a year's course of the Bayer-made drug. However, the cost of the Indian version of the generic drug would be around $2,800 (£1,700).[74] Notes1. ^{{cite press release|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109030.htm |title=FDA Approves Nexavar for Patients with Inoperable Liver Cancer |publisher=FDA |date=November 19, 2007 |accessdate=November 10, 2012}} 2. ^{{cite journal | vauthors = Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M | title = CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations | journal = Oncogene | volume = 28 | issue = 1 | pages = 85–94 |date=January 2009 | pmid = 18794803 | pmc = 2898184 | doi = 10.1038/onc.2008.362 }} 3. ^{{cite journal | vauthors = Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M | title = Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling | journal = Mol. Cancer Ther. | volume = 7 | issue = 10 | pages = 3129–40 |date=October 2008 | pmid = 18852116 | doi = 10.1158/1535-7163.MCT-08-0013 }} 4. ^{{cite journal | author = Zhang Y | title = Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. | journal = J Mol Med Rep | volume = 9 | issue = 1|date=Jan 2014 | pmid = 24213221 | url = http://www.spandidos-publications.com/mmr/9/1/83 | pages = 83–90 | doi=10.3892/mmr.2013.1781}} 5. ^{{cite journal | author = Gauthier A | title = Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.. | journal = Hepatol Res | volume = 43 | issue = 2 |date=Feb 2013 | pmid = 23145926 | pages = 147–154 | doi=10.1111/j.1872-034x.2012.01113.x | pmc=3574194}} 6. ^{{cite web|title=Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=26 December 2013|url=http://reference.medscape.com/drug/nexavar-sorafenib-342260#showall}} 7. ^{{cite web|title=NEXAVAR (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]|work=DailyMed|publisher=Bayer HealthCare Pharmaceuticals Inc.|date=November 2013|accessdate=26 December 2013|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b50667e4-5ebc-4968-a646-d605058dbef0}} 8. ^{{cite web|title=Nexavar 200mg film-coated tablets - Summary of Product Characteristics (SPC) - (eMC)|work=electronic Medicines Compendium|publisher=Bayer plc|date=27 March 2013|accessdate=26 December 2013|url=http://www.medicines.org.uk/emc/medicine/18520/SPC/Nexavar+200mg+film-coated+tablets/}} 9. ^1 2 {{cite web|title=PRODUCT INFORMATION NEXAVAR® (sorafenib tosylate)|work=TGA eBusiness Services|publisher=Bayer Australia Ltd|date=12 December 2012|accessdate=26 December 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07403-3|format=PDF}} 10. ^{{cite journal|author1 = Escudier, B|author2 = Eisen, T |author3 = Stadler, WM |author4 = Szczylik, C |author5 = Oudard, S |author6 = Siebels, M |author7 = Negrier, S |author8 = Chevreau, C |author9 = Solska, E |author10 = Desai, AA |author11 = Rolland, F |author12 = Demkow, T |author13 = Hutson, TE |author14 = Gore, M |author15 = Freeman, S |author16 = Schwartz, B |author17 = Shan, M |author18 = Simantov, R |author19 = Bukowski, RM | title = Sorafenib in advanced clear-cell renal-cell carcinoma | journal = New England Journal of Medicine | volume = 356 | issue = 2 | pages = 125–34 |date=January 2007 | pmid = 17215530 |doi = 10.1056/NEJMoa060655 }} 11. ^1 {{cite journal | author = Llovet| title = Sorafenib in Advanced Hepatocellular Carcinoma | journal = New England Journal of Medicine | volume = 359 | issue=4 | pages = 378–90 |year = 2008| doi=10.1056/NEJMoa0708857 | pmid=18650514|display-authors=etal| citeseerx = 10.1.1.531.1130 }} 12. ^1 2 {{cite journal | vauthors = Keating GM, Santoro A | title = Sorafenib: a review of its use in advanced hepatocellular carcinoma | journal = Drugs | volume = 69 | issue = 2 | pages = 223–40 | year = 2009 | pmid = 19228077|doi = 10.2165/00003495-200969020-00006 }} 13. ^{{cite journal | vauthors = Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF | title = Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma| journal = J. Clin. Oncol. | volume = 29 | issue = 30 | pages = 3960–7 |date=October 2011 | pmid = 21911714 | doi = 10.1200/JCO.2011.37.1021 | pmc = 4829081 }} 14. ^1 {{cite web|title=Pharmaceutical Benefits Scheme (PBS) -SORAFENIB|work=Pharmaceutical Benefits Scheme|publisher=Australian Government Department of Health|accessdate=27 December 2013|url=http://www.pbs.gov.au/medicine/item/9380Q}} 15. ^{{cite web|url=http://www.cancer.gov/cancertopics/druginfo/fda-sorafenib-tosylate|title= FDA Approval for Sorafenib Tosylate|author=|date=5 October 2006|website=National Cancer Institute}} 16. ^{{cite web|url=https://www.medpagetoday.com/meetingcoverage/asco/39545|title=ASCO: Sorafenib Halts Resistant Thyroid Cancer|author=|date=4 June 2013|website=www.medpagetoday.com}} 17. ^{{cite web|title=Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis|url=http://clinicaltrials.gov/show/NCT02066181|website=Clinicaltrials.gov}} 18. ^{{cite journal|last1=Gounder|first1=MM|last2=Lefkowitz|first2=RA|last3=Keohan|first3=ML|last4=D'Adamo|first4=DR|last5=Hameed|first5=M|last6=Antonescu|first6=CR|last7=Singer|first7=S|last8=Stout|first8=K|last9=Ahn|first9=L|last10=Maki|first10=RG|title=Activity of Sorafenib against desmoid tumor/deep fibromatosis.|journal=Clinical Cancer Research|date=15 June 2011|volume=17|issue=12|pages=4082–90|pmid=21447727|doi=10.1158/1078-0432.ccr-10-3322|pmc=3152981}} 19. ^Low blood phosphate levels 20. ^Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds 21. ^High blood pressure 22. ^Including abdominal pain, headache, tumour pain, etc. 23. ^Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis) 24. ^{{cite web|title=Chemotherapy-Induced Nausea and Vomiting Treatment & Management|work=Medscape Reference|publisher=WebMD|date=3 July 2012|accessdate=26 December 2013|url=http://emedicine.medscape.com/article/1355706-treatment#showall}} 25. ^Low level of white blood cells in the blood 26. ^Low level of neutrophils in the blood 27. ^Low level of red blood cells in the blood 28. ^Low level of plasma cells in the blood 29. ^Low blood calcium 30. ^Low blood potassium 31. ^Hearing ringing in the ears 32. ^Heart attack 33. ^Lack of blood supply for the heart muscle 34. ^Mouth swelling, also dry mouth and glossodynia 35. ^Indigestion 36. ^Not being able to swallow 37. ^Sore joints 38. ^Muscle aches 39. ^Kidney failure 40. ^Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage 41. ^Including skin reactions and urticaria (hives) 42. ^Underactive thyroid 43. ^Overactive thyroid 44. ^Low blood sodium 45. ^Runny nose 46. ^Pneumonitis, radiation pneumonitis, acute respiratory distress, etc. 47. ^Swelling of the pancreas 48. ^Swelling of the stomach 49. ^Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds 50. ^Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body 51. ^Swelling of the gallbladder 52. ^Swelling of the bile duct 53. ^1 2 A potentially fatal skin reaction 54. ^A fairly benign form of skin cancer 55. ^{{cite journal|last=Hagopian|first=Benjamin|title=Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report|journal=Journal of Medical Cases|date=August 2010|volume=1|issue=1|pages=1–3|doi=10.4021/jmc112e|url=http://www.journalmc.org/index.php/JMC/article/view/11/9|accessdate=11 February 2014}} 56. ^A potentially fatal abnormality in the electrical activity of the heart 57. ^Swelling of the skin and mucous membranes 58. ^A potentially fatal allergic reaction 59. ^Swelling of the liver 60. ^The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys 61. ^FDA Approval letter for use of sorafenib in advanced renal cancer 62. ^European Commission – Enterprise and industry. Nexavar {{webarchive|url=https://web.archive.org/web/20080201001404/http://ec.europa.eu/enterprise/pharmaceuticals/register/h342.htm |date=2008-02-01 }}. Retrieved April 24, 2007. 63. ^{{cite press release|title=Nexavar® (Sorafenib) Approved for Hepatocellular Carcinoma in Europe|url=http://www.pslgroup.com/news/content.nsf/medicalnews/852571020057CCF685257384005A45B1?OpenDocument&id=&count=10|publisher=Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals|date=October 30, 2007|accessdate=November 10, 2012|deadurl=yes|archiveurl=https://web.archive.org/web/20120206215725/http://www.pslgroup.com/news/content.nsf/medicalnews/852571020057CCF685257384005A45B1?OpenDocument&id=&count=10|archivedate=February 6, 2012|df=}} 64. ^FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma 65. ^1 {{cite web|url=http://news.bbc.co.uk/1/hi/health/8367614.stm |publisher=BBC News |title=Liver drug 'too expensive' |date=November 19, 2009|accessdate=November 10, 2012}} 66. ^http://www.lawyerscollective.org/updates/supreme-court-says-no-to-bayer-upholds-compulsory-license-on-nexavar.html 67. ^{{cite web |url=http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf |title=Archived copy |accessdate=2012-04-02 |deadurl=yes |archiveurl=https://web.archive.org/web/20120321173251/http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf |archivedate=2012-03-21 |df= }} 68. ^{{cite journal |doi=10.1038/483250a |title=Seven days: 9–15 March 2012 |year=2012 |journal=Nature |volume=483 |issue=7389 |pages=250–1}} 69. ^{{cite web|title=India Patents (Amendment) Act, 2005|url=http://www.wipo.int/wipolex/en/text.jsp?file_id=128116|publisher=WIPO|accessdate=16 January 2013}} 70. ^{{cite web|url=http://www.medscape.com/viewarticle/573511|title=Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients|author=|date=|website=login.medscape.com}} 71. ^{{Cite journal|last=Ciccone|first=Marcia A.|last2=Maoz|first2=Asaf|last3=Casabar|first3=Jennifer K.|last4=Machida|first4=Hiroko|last5=Mabuchi|first5=Seiji|last6=Matsuo|first6=Koji|date=July 2016|title=Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature|journal=Expert Opinion on Investigational Drugs|volume=25|issue=7|pages=781–796|doi=10.1080/13543784.2016.1181748|issn=1744-7658|pmid=27101098}} 72. ^{{ClinicalTrialsGov|NCT00329719|Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma}} 73. ^{{cite journal | pmc = 3152981 | pmid=21447727 | doi=10.1158/1078-0432.CCR-10-3322 | volume=17 | issue=12 | title=Activity of Sorafenib against desmoid tumor/deep fibromatosis. | date=Jun 2011 | journal=Clin Cancer Res | pages=4082–90 | last1 = Gounder | first1 = MM | last2 = Lefkowitz | first2 = RA | last3 = Keohan | first3 = ML | last4 = D'Adamo | first4 = DR | last5 = Hameed | first5 = M | last6 = Antonescu | first6 = CR | last7 = Singer | first7 = S | last8 = Stout | first8 = K | last9 = Ahn | first9 = L | last10 = Maki | first10 = RG}} 74. ^{{cite news|title='We didn't make this medicine for Indians… we made it for western patients who can afford it'|url=http://www.dailymail.co.uk/news/article-2545360/Pharmaceutical-chief-tries-stop-India-replicating-cancer-treatment.html|newspaper=Daily Mail Reporter|date=24 Jan 2014}} References{{reflist|colwidth=35em}}External links
10 : Orphan drugs|Receptor tyrosine kinase inhibitors|Chloroarenes|Trifluoromethyl compounds|Anilines|Ureas|Phenol ethers|Pyridines|Carboxamides|Cancer treatments |
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