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Gefitinib
Systematic (IUPAC) name
N-(3-chloro-4-fluoro-phenyl)-7-methoxy-
6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
Identifiers
CAS number 184475-35-2
ATC code L01XE02
PubChem 123631
DrugBank APRD00997
Chemical data
Formula C22H24ClFN4O3 
Mol. mass 446.902 g/mol
Pharmacokinetic data
Bioavailability 59% (oral)
Protein binding 90%
Metabolism Hepatic (mainly CYP3A4)
Half life 6–49 hours
Excretion Faecal
Therapeutic considerations
Pregnancy cat. C (Au), D (U.S.)
Legal status S4 (Au), POM (UK), ℞-only (U.S.)
Routes Oral
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Gefitinib (INN) (pronounced /ɡɛˈfɪtɨnɪb/) (Iressa) is a drug used in the treatment of certain types of cancer. Gefitinib is an EGFR inhibitor, like erlotinib, selectively targeting proteins in malignant cells. It is marketed by AstraZeneca and Teva.

Contents

Mechanism of action

Gefitinib is the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain. Thus gefitinib is an EGFR inhibitor. The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature source.

EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic Ras signalling cascade, eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.[1][2] These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, adenocarcinoma is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma).

Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited, and malignant cells are inhibited.[3]

Clinical uses

Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy.

While gefitinib has yet to be proven to be effective in other cancers, there is potential for its use in the treatment of other cancers where EGFR overexpression is involved.

In 2004, AstraZeneca informed the United States Food and Drug Administration (FDA) that a large randomized study failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC).[4] Whether progression-free survival is prolonged is not clear from this statement. AstraZeneca also withdrew their application to market gefitinib in Europe shortly after this announcement.

Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib. Given the lack of survival advantage for gefitinib and the positive results for erlotinib, erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response).

Studies

A study conducted in 2006 involved 1,217 patients in advanced stages of cancer who had not previously received chemotherapy, and who had never smoked or who had smoked very little. The results showed 25 percent of patients on gefitinib had no cancer growth within 12 months, compared with 7 percent on chemotherapy. Final overall survival data from this study will not be available until 2010, but the median overall survival is slightly better with gefitinib than with chemotherapy.[5]

Genzyme test

On September 26 2005, Genzyme Corp. announced that it would market a test to detect EGFR mutations, designed to help predict which lung cancer patients may respond best to some therapies, including gefitinib and erlotinib. This method is used to identify ahead of time which patients may respond to medications in this drug class.[1]

The test, expected to cost about $975, examines the genetics of tumors removed for biopsy for mutations that make them susceptible to treatment.

The EGFR mutation test may also help Genentech and AstraZeneca win regulatory approval for use of their drugs as initial therapies. Currently the TK inhibitors are approved for use only after other drugs fail. In the case of gefitinib, the drug works only in about 10% of patients with advanced non-small cell lung cancer, the most common type of lung cancer. This led the Food and Drug Administration this summer to partially withdraw the drug in the U.S., no longer allowing its prescription for new patients. Template:As of ? The drug remains on the market in Europe.

Adverse effects

As gefitinib is a selective chemotherapeutic agent, its tolerability profile is far superior to previous cytotoxic agents. Adverse drug reactions (ADRs) do still occur however, but may be preferable to the fatal consequences of not taking the therapy.

Acne is reported very commonly. Other common adverse effects (≥1% of patients) include: diarrhoea, nausea, vomiting, anorexia, stomatitis, dehydration, skin reactions, paronychia, asymptomatic elevations of liver enzymes, asthenia, conjunctivitis, blepharitis.[6]

Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, corneal erosion, aberrant eyelash and hair growth.[6]

See also

References

  1. ^ Pao W, Miller V, Zakowski M, et al. (September 2004). "EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib". Proceedings of the National Academy of Sciences of the United States of America 101 (36): 13306–11. doi:10.1073/pnas.0405220101. PMID 15329413. 
  2. ^ Sordella R, Bell DW, Haber DA, Settleman J (August 2004). "Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways". Science (New York, N.Y.) 305 (5687): 1163–7. doi:10.1126/science.1101637. PMID 15284455. 
  3. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  4. ^ AstraZeneca (2004-12-17). "Gefitinib (Iressa TM) lung cancer isel trial shows no overall survival advantage in a highly refractory population". Press release. Archived from the original on 2008-02-11. http://web.archive.org/web/20080211121719/http://www.astrazeneca.com/pressrelease/4245.aspx. Retrieved 2009-07-02. 
  5. ^ Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Eng J Med 2009; 361. 10.1056/NEJMoa0810699.
  6. ^ a b Rossi S, editor. Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook; 2004. ISBN 0-9578521-4-2.







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