Sorafenib

Sorafenib
Systematic (IUPAC) name
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]
phenoxy]-N-methyl-pyridine-2-carboxamide
Clinical data
Trade names Nexavar
AHFS/Drugs.com monograph
MedlinePlus a607051
Licence data EMA:LinkUS FDA:link
Pregnancy cat. D(AU) D(US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 29-49%
Protein binding 99.5%
Metabolism Hepatic oxidation and glucuronidation (CYP3A4-mediated)
Half-life 25–48 hours
Excretion Fecal (77%) and renal (19%)
Identifiers
CAS number 284461-73-0 Y
ATC code L01XE05
PubChem CID 216239
DrugBank APRD01304
ChemSpider 187440 Y
UNII 9ZOQ3TZI87 Y
KEGG D08524 Y
ChEBI CHEBI:50924 Y
ChEMBL CHEMBL1336 Y
Synonyms Nexavar
Sorafenib tosylate
Chemical data
Formula C21H16ClF3N4O3 
Mol. mass 464.825 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).

Contents

Pharmacology

Sorafenib (a bi-aryl urea[2]) is a small molecular inhibitor of several Tyrosine protein kinases (VEGFR and PDGFR) and Raf kinases (more avidly C-Raf than B-Raf).[3][4]

(Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor. )

Sorafenib is/was unique in targeting the Raf/Mek/Erk pathway (MAP Kinase pathway).[5]

Sorafenib inhibits some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf and mutant B-Raf).[2]

Approvals

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,[6] and received European Commission marketing authorization in July 2006,[7] 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,[8] and FDA approval for this indication followed in November 2007.[9]

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.[10] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.[10]

Clinical studies

Kidney

An article in The New England Journal of Medicine, published January 2007, showed 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] A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.[12]

Liver

At ASCO 2007, results from the SHARP trial were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was 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. 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. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.[2]

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.[2]

Thyroid cancer

A phase 3 clinical trial has started recruiting (Nov 2009) to use sorafenib for non-responsive thyroid cancer.[13]

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.[14]

Brain (Recurrent Glioblastoma)

There is a phase I/II study at the Mayo Clinic [15] of Sorafenib and CCI-779 (Temsirolimus) for recurrent glioblastoma.

Adverse effects

Adverse effects of sorafenib include skin rash, hand-foot skin reactions, diarrhea, and hypertension. A case of diffuse yellow discoloration of the skin has been reported.[16] Sorafenib has also been implicated in the development of reversible posterior leukoencephalopathy syndrome and reversible erythrocytosis.[17]

References

  1. ^ "FDA Approves Nexavar for Patients with Inoperable Liver Cancer". FDA.gov. 2007-11-19. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109030.htm. Retrieved 2011-09-01. 
  2. ^ a b c d Keating GM, Santoro A. (2009). "Sorafenib: A Review of its Use in Advanced Hepatocellular Carcinoma". Drugs 69 (2): 223–240. doi:10.2165/00003495-200969020-00006. http://adisonline.com/drugs/abstract/2009/69020/Sorafenib__A_Review_of_its_Use_in_Advanced.6.aspx. 
  3. ^ K. S. M. Smalley, M. Xiao, J. Villanueva, T. K. Nguyen, K. T. Flaherty, R. Letrero, P. Van Belle, D. E. Elder, Y. Wang, K. L. Nathanson and M. Herlyn (8 January 2009). "CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations". Oncogene 28: 85–94. doi:10.1038/onc.2008.362. ISSN 0950-9232. 
  4. ^ Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008). "Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling". Molecular Cancer Therapeutics 7 (10): 3129–40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116. 
  5. ^ "Sorafenib Sunitinib differences". http://www.healthvalue.net/SorafenibSunitinibdifferences.html. Retrieved August 15, 2007.  Undated? unreliable?
  6. ^ FDA Approval letter for use of sorafenib in advanced renal cancer
  7. ^ European Commission - Enterprise and industry. Nexavar. Retrieved April 24, 2007.
  8. ^ "Nexavar (Sorafenib) Approved for Hepatocellular Carcinoma in Europe". 2007. http://www.pslgroup.com/news/content.nsf/medicalnews/852571020057CCF685257384005A45B1?OpenDocument&id=&count=10. 
  9. ^ FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
  10. ^ a b BBC News: Liver drug 'too expensive'
  11. ^ Escudier B, Eisen T, Stadler WM, et al. (January 2007). "Sorafenib in advanced clear-cell renal-cell carcinoma". N. Engl. J. Med. 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530. 
  12. ^ Walid MS, Johnston KW (2009). "Successful treatment of a brain-metastasized renal cell carcinoma". Ger Med Sci 7: Doc28. doi:10.3205/000087. PMC 2775194. PMID 19911072. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2775194. 
  13. ^ http://www.lifescience-online.com/,18181?portalPage=Lifescience+Today.News "Phase 3 Trial of Nexavar in Patients With Non-Responsive Thyroid Cancer"
  14. ^ http://www.medscape.com/viewarticle/573511 "Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients"
  15. ^ "Treatment with Sorafenib (Nexavar) and CCI-779 (Temsirolimus) in patients with recurrent Glioblastoma". http://clinicaltrials.mayo.edu/clinicaltrialdetails.cfm?trial_id=100936&title=Sorafenib%20and%20Temsirolimus%20in%20Treating%20Patients%20With%20Recurrent%20Glioblastoma. 
  16. ^ Dasanu CA, et al. (March 2007). "Yellow skin discoloration associated with sorafenib use for treatment of metastatic renal cell carcinoma". Southern Medical Journal 100 (3): 328–30. PMID 17396743. 
  17. ^ Alexandrescu DT, McClure R, Farzanmehr H, Dasanu CA (August 2008). "Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib". J. Clin. Oncol. 26 (24): 4047–8. doi:10.1200/JCO.2008.18.3525. PMID 18711201. http://www.jco.org/cgi/pmidlookup?view=long&pmid=18711201. 

External links