Sorafenib

Sorafenib

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Systematic (IUPAC) name
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Nexavar US FDA: Sorafenib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	29-49%
Protein binding	99.5%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4-mediated)
Biological half-life	25–48 hours
Excretion	Fecal (77%) and renal (19%)
Identifiers
CAS Number	284461-73-0
ATC code	L01XE05 (WHO)
PubChem	CID 216239
DrugBank	APRD01304
Synonyms	Nexavar Sorafenib tosylate
Chemical data
Formula	C21H16ClF3N4O3
Molar mass	464.825 g/mol[[]]

Sorafenib (marketed as Nexavar by Bayer), is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).

Pharmacology

Sorafenib is a small molecular inhibitor of several Tyrosine protein kinases.

(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. A growing number of drugs target most of these pathways.)

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

Approval

Renal cancer

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

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

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). A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.

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 (ie 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 hepatocelluar 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.

Lung

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

Thyroid cancer

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

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. Sorafenib has also been implicated in the development of reversible posterior leukoencephalopathy syndrome and reversible erythrocytosis..

External links

• Nexavar.com – Manufacturer's website
• Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
• Patient Information from FDA
• Sorafenib in Treating Patients With Soft Tissue Sarcomas
• ClinicalTrials.gov NCT00217399 - Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer

• Cipla launches Nexavar generic at 1/10th of Bayer's price

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