chemistry

Sorafenib

Sorafenib is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Sorafenib rather than just read about it. In short: Sorafenib, sold under the brand name Nexavar, 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…

Key takeaways

Sorafenib belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Sorafenib to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Sorafenib from memory before moving on to harder problems.

Reference excerpt

Sorafenib, sold under the brand name Nexavar, 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. Of the RAF kinases, sorafenib is more selective for c-Raf than B-RAF. (See BRAF (gene)#Sorafenib for details the drug's interaction with B-Raf.) Sorafenib treatment induces autophagy, 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.

Medical uses Sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC), thyroid cancer and Acute Myeloid Leukaemia with FLT3-ITD mutation..

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). 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.

Liver cancer At ASCO 2007, results from the SHARP trial 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. 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. 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. In Australia this is the only indication for which sorafenib is listed on the PBS and hence the only government-subsidised indication for sorafenib. Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.

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. 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.

Acute Myeloid Leukaemia In patients with FLT3-ITD mutated AML, sorafenib can be used as a maintenance therapy post-Allogeneic haematopoietic stem-cell transplantation to target any residual disease that could remain in the bone marrow.

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

Common (1-10% frequency)

Transient increase in transaminase 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, 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 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. In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason. 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₹280,000 (US$2,900). Natco Pharma will sell 120 tablets for ₹8,800 (US$91), while still paying a 6% royalty to Bayer. The royalty was later raised to 7% on appeal by Bayer. 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.

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).

Research

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Sorafenib

Start with the simplest possible case. Write down what Sorafenib claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Sorafenib before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Sorafenib ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Sorafenib

In research: Sorafenib appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Sorafenib in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Sorafenib is common in secondary-school and first-year university syllabi. It links to neighbouring topics 1-Chloro-2-(trifluoromethyl)benzene derivatives, 4-Aminophenyl compounds, 4-Hydroxyphenyl compounds, so understanding it makes those chapters shorter.
In everyday life: Look for Sorafenib outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Sorafenib in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Sorafenib means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Sorafenib out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Sorafenib in simple terms?

Why does Sorafenib matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Sorafenib?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Sorafenib.