Sorafenib Explained

Verifiedrevid:464405524
Width:300
Width2:250
Tradename:Nexavar, others
Dailymedid:Sorafenib
Licence Eu:yes
Licence Us:Sorafenib
Pregnancy Au:D
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:EX02
Legal Au:S4
Legal Ca:Rx-only
Legal Uk:POM
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[1]
Bioavailability:38–49%
Protein Bound:99.5%
Metabolism:Liver oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
Elimination Half-Life:25–48 hours
Excretion:Feces (77%) and urine (19%)
Cas Number:284461-73-0
Pubchem:216239
Iuphar Ligand:5711
Drugbank:DB00398
Chemspiderid:187440
Unii:9ZOQ3TZI87
Kegg:D08524
Kegg2:D06272
Chebi:50924
Chembl:1336
Pdb Ligand:BAX
Synonyms:Sorafenib tosylate
Iupac Name:4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]
phenoxy]-N-methyl-pyridine-2-carboxamide
C:21
H:16
Cl:1
F:3
N:4
O:3
Smiles:CNC(=O)c1cc(ccn1)Oc2ccc(cc2)NC(=O)Nc3ccc(c(c3)C(F)(F)F)Cl
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:MLDQJTXFUGDVEO-UHFFFAOYSA-N

Sorafenib, sold under the brand name Nexavar,[2] 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 action

Sorafenib is a protein kinase inhibitor with activity against many protein kinases, including VEGFR, PDGFR and RAF kinases.[3] Of the RAF kinases, sorafenib is more selective for c-Raf than B-RAF.[4] (See BRAF (gene)#Sorafenib for details the drug's interaction with B-Raf.)

Sorafenib treatment induces autophagy,[5] which may suppress tumor growth. Based on its 1,3-disubstituted urea structure, sorafenib is also a potent soluble epoxide hydrolase inhibitor and this activity likely reduces the severity of its adverse effects.[6]

Medical uses

Sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.[7] [8] [9] [10]

Kidney cancer

Clinical 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).[11]

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.[10]

Liver cancer

At ASCO 2007, results from the SHARP trial[12] 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.[12] Because of this trial sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.

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.[13]

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.[14]

In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only government-subsidised indication for sorafenib.[15] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.[10]

Thyroid cancer

On 22 November 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.[16]

The phase III 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.[17]

Adverse effects

Adverse effects by frequency
Note: Potentially serious side effects are in bold.
Very common (>10% frequency)

Common (1-10% frequency)

Uncommon (0.1-1% frequency)

Rare (0.01-0.1% frequency)

History

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,[60] and received European Commission marketing authorization in July 2006,[61] both for use in the treatment of advanced renal cancer.

Liver cancer

The 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,[62] and FDA approval for this indication followed in November 2007.[63]

In November 2009, the UK's National Institute for 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.[64] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.[64]

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. Natco Pharma will sell 120 tablets for, while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer.[65] [66] [67] Under the Patents Act, 1970 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.[68]

Society and culture

Nexavar controversy

In January 2014, Bayer's CEO Marijn Dekkers allegedly stated that Nexavar was developed for "Western patients who can afford it, not for Indians". A kidney cancer patient would pay $96,000 (£58,000) for a year's course of the Bayer-made drug, whereas the cost of the Indian version of the generic drug would be around $2,800 (£1,700).[69]

Research

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.[70]

Ovarian cancer

Sorafenib 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 of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.

Desmoid tumor (aggressive fibromatosis)

A study performed in 2008 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 the condition.[72]

A phase III clinical trial is 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.[73] [74] [75]

See also

External links

Notes and References

  1. Web site: Nexavar EPAR . European Medicines Agency (EMA) . 17 September 2018 . 18 September 2022 . 14 October 2021 . https://web.archive.org/web/20211014220703/https://www.ema.europa.eu/en/medicines/human/EPAR/nexavar . live .
  2. FDA Approves Nexavar for Patients with Inoperable Liver Cancer . FDA . 19 November 2007 . 10 November 2012 . 2 January 2017 . https://web.archive.org/web/20170102045657/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109030.htm . dead .
  3. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M . Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling . Molecular Cancer Therapeutics . 7 . 10 . 3129–3140 . October 2008 . 18852116 . 10.1158/1535-7163.MCT-08-0013 . free .
  4. Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M . CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations . Oncogene . 28 . 1 . 85–94 . January 2009 . 18794803 . 2898184 . 10.1038/onc.2008.362 .
  5. Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X . Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways . Molecular Medicine Reports . 9 . 1 . 83–90 . January 2014 . 24213221 . 10.3892/mmr.2013.1781 . free .
  6. Book: Singh N, Hammock B . Offermanns S, Rosenthal W . Encyclopedia of Molecular Pharmacology . Springer, Cham . 30 March 2020 . Soluble Epoxide Hydrolase . 10.1007/978-3-030-21573-6 . 10138/346042 . 978-3-030-21573-6. 171511522 .
  7. Web site: Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. 26 December 2013. 27 December 2013. https://web.archive.org/web/20131227052838/http://reference.medscape.com/drug/nexavar-sorafenib-342260#showall. live.
  8. Web site: Nexavar (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]]. DailyMed. Bayer HealthCare Pharmaceuticals Inc.. November 2013. 26 December 2013. 20 September 2015. https://web.archive.org/web/20150920064541/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b50667e4-5ebc-4968-a646-d605058dbef0. live.
  9. Web site: Nexavar 200mg film-coated tablets - Summary of Product Characteristics (SPC) - (eMC). electronic Medicines Compendium. Bayer plc. 27 March 2013. 26 December 2013. 27 December 2013. https://web.archive.org/web/20131227025137/http://www.medicines.org.uk/emc/medicine/18520/SPC/Nexavar+200mg+film-coated+tablets/. live.
  10. Web site: PRODUCT INFORMATION NEXAVAR (sorafenib tosylate). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. 26 December 2013. PDF. 14 January 2016. https://web.archive.org/web/20160114035221/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07403-3. live.
  11. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM . Sorafenib in advanced clear-cell renal-cell carcinoma . The New England Journal of Medicine . 356 . 2 . 125–134 . January 2007 . 17215530 . 10.1056/NEJMoa060655 . free .
  12. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J . Sorafenib in advanced hepatocellular carcinoma . The New England Journal of Medicine . 359 . 4 . 378–390 . July 2008 . 18650514 . 10.1056/NEJMoa0708857 . 10.1.1.531.1130 .
  13. Keating GM, Santoro A . Sorafenib: a review of its use in advanced hepatocellular carcinoma . Drugs . 69 . 2 . 223–240 . 2009 . 19228077 . 10.2165/00003495-200969020-00006 .
  14. Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF . Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma . Journal of Clinical Oncology . 29 . 30 . 3960–3967 . October 2011 . 21911714 . 4829081 . 10.1200/JCO.2011.37.1021 .
  15. Web site: Pharmaceutical Benefits Scheme (PBS) -SORAFENIB. Pharmaceutical Benefits Scheme. Australian Government Department of Health. 27 December 2013. 27 December 2013. https://web.archive.org/web/20131227071546/http://www.pbs.gov.au/medicine/item/9380Q. live.
  16. Web site: FDA Approval for Sorafenib Tosylate. 5 October 2006. National Cancer Institute. 27 November 2013. 6 April 2015. https://web.archive.org/web/20150406012049/http://www.cancer.gov/cancertopics/druginfo/fda-sorafenib-tosylate. live.
  17. News: ASCO: Sorafenib Halts Resistant Thyroid Cancer. 4 June 2013. www.medpagetoday.com. 21 December 2018. 23 March 2021. https://web.archive.org/web/20210323215502/https://www.medpagetoday.com/MeetingCoverage/ASCO/39545. live.
  18. Low blood phosphate levels
  19. Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
  20. High blood pressure
  21. Including abdominal pain, headache, tumour pain, etc.
  22. Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
  23. Web site: Chemotherapy-Induced Nausea and Vomiting Treatment & Management. Medscape Reference. WebMD. 3 July 2012. 26 December 2013. 27 December 2013. https://web.archive.org/web/20131227052153/http://emedicine.medscape.com/article/1355706-treatment#showall. live.
  24. Low level of white blood cells in the blood
  25. Low level of neutrophils in the blood
  26. Low level of red blood cells in the blood
  27. Low level of plasma cells in the blood
  28. Low blood calcium
  29. Low blood potassium
  30. Hearing ringing in the ears
  31. Heart attack
  32. Lack of blood supply for the heart muscle
  33. Mouth swelling, also dry mouth and glossodynia
  34. Indigestion
  35. Not being able to swallow
  36. Sore joints
  37. Muscle aches
  38. Kidney failure
  39. Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
  40. Including skin reactions and urticaria (hives)
  41. Underactive thyroid
  42. Overactive thyroid
  43. Low blood sodium
  44. Runny nose
  45. [Pneumonitis]
  46. Swelling of the pancreas
  47. Swelling of the stomach
  48. Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
  49. 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
  50. Swelling of the gallbladder
  51. Swelling of the bile duct
  52. A potentially fatal skin reaction
  53. A fairly benign form of skin cancer
  54. Hagopian B . Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report. Journal of Medical Cases. August 2010. 1. 1. 1–3. 10.4021/jmc112e. free.
  55. A potentially fatal abnormality in the electrical activity of the heart
  56. Swelling of the skin and mucous membranes
  57. A potentially fatal allergic reaction
  58. Swelling of the liver
  59. The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys
  60. Web site: FDA Approval letter for use of sorafenib in advanced renal cancer . 19 November 2009 . 30 March 2021 . https://web.archive.org/web/20210330040359/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021923ltr.pdf . live .
  61. Web site: . Enterprise and Industry. . Nexavar . https://web.archive.org/web/20080201001404/http://ec.europa.eu/enterprise/pharmaceuticals/register/h342.htm . 1 February 2008 . 24 April 2007 .
  62. Nexavar (Sorafenib) Approved for Hepatocellular Carcinoma in Europe. Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. 30 October 2007. 10 November 2012. dead. https://web.archive.org/web/20120206215725/http://www.pslgroup.com/news/content.nsf/medicalnews/852571020057CCF685257384005A45B1?OpenDocument&id=&count=10. 6 February 2012.
  63. Web site: FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma . 19 November 2009 . 31 March 2021 . https://web.archive.org/web/20210331020338/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2007/021923s004,s005,s006,s007.pdf . live .
  64. Web site: Liver drug 'too expensive' . BBC News . 19 November 2009 . 10 November 2012 . 11 September 2017 . https://web.archive.org/web/20170911102550/http://news.bbc.co.uk/1/hi/health/8367614.stm . live .
  65. Web site: » Supreme Court says no to Bayer, upholds compulsory license on Nexavar. dead . https://web.archive.org/web/20150217113537/http://www.lawyerscollective.org/updates/supreme-court-says-no-to-bayer-upholds-compulsory-license-on-nexavar.html . 17 February 2015 .
  66. Web site: Application for Compulsory Licence Under Section 84(1) of the Patents Act, 1970 in Respect of Patent No.215758 . Controller of Patents Mumbai . 2 April 2012 . dead . https://web.archive.org/web/20120321173251/http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf . 21 March 2012 .
  67. 10.1038/483250a . Indian generics . 9–15 March 2012 . Nature . 483 . 7389 . 250–1. 2012Natur.483..250. . free .
  68. Web site: India Patents (Amendment) Act, 2005. WIPO. 16 January 2013. 16 January 2013. https://web.archive.org/web/20130116013515/http://www.wipo.int/wipolex/en/text.jsp?file_id=128116. live.
  69. Web site: Bloomberg's viral misquote . Chittum R . 29 January 2014 . Columbia Journalism Review . 12 September 2019 . 10 February 2021 . https://web.archive.org/web/20210210092049/https://archives.cjr.org/the_audit/bloombergs_viral_misquote_1.php . live .
  70. Web site: Chustecka Z . April 25, 2008 . Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients. MedScape . 29 October 2010. 29 August 2021. https://web.archive.org/web/20210829064212/https://www.medscape.com/viewarticle/573511. live.
  71. Ciccone MA, Maoz A, Casabar JK, Machida H, Mabuchi S, Matsuo K . Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature . Expert Opinion on Investigational Drugs . 25 . 7 . 781–796 . July 2016 . 27101098 . 7534810 . 10.1080/13543784.2016.1181748 . 28717797 .
  72. Gounder MM, Lefkowitz RA, Keohan ML, D'Adamo DR, Hameed M, Antonescu CR, Singer S, Stout K, Ahn L, Maki RG . Activity of Sorafenib against desmoid tumor/deep fibromatosis . Clinical Cancer Research . 17 . 12 . 4082–4090 . June 2011 . 21447727 . 3152981 . 10.1158/1078-0432.CCR-10-3322 .
  73. Web site: Sorafenib Tosylate in Treating Patients With Desmoid Tumors or Aggressive Fibromatosis. Clinicaltrials.gov. 12 November 2014. 13 November 2014. https://web.archive.org/web/20141113012518/http://clinicaltrials.gov/show/NCT02066181. live.
  74. Gounder MM, Lefkowitz RA, Keohan ML, D'Adamo DR, Hameed M, Antonescu CR, Singer S, Stout K, Ahn L, Maki RG . Activity of Sorafenib against desmoid tumor/deep fibromatosis . Clinical Cancer Research . 17 . 12 . 4082–4090 . June 2011 . 21447727 . 3152981 . 10.1158/1078-0432.ccr-10-3322 .
  75. Mangla A, Agarwal N, Schwartz G . Desmoid Tumors: Current Perspective and Treatment . Current Treatment Options in Oncology . 25 . 2 . 161–175 . February 2024 . 38270798 . 10873447 . 10.1007/s11864-024-01177-5 . free .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Sorafenib".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.