Erlotinib

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Erlotinib
Systematic (IUPAC) name
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
quinazolin-4-amine
Identifiers
CAS number 183321-74-6
ATC code L01XE03
PubChem 176870
DrugBank APRD00951
ChemSpider 154044
Chemical data
Formula C22H23N3O4 
Mol. mass 393.436 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Licence data

EU EMEA:link, US FDA:link
Pregnancy cat.

D(US)
Legal status

POM(UK) ℞-only(US)
Routes Oral
 Yes check.svgY(what is this?)  (verify)

Erlotinib hydrochloride (originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche under the tradename Tarceva.

Contents

[edit] Mechanism

Erlotinib is an EGFR inhibitor. Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.[1] For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change in their intracellular structure, exposing a further binding site for binding proteins that cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped.

[edit] Development

Erlotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. It has been approved for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen. In November 2005, the U.S. Food and Drug Administration (FDA) approved the use of erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.[2]

A test for the EGFR mutation in cancer patients has been developed by Genzyme. This may predict who will respond to erlotinib and other tyrosine kinase inhibitors. It is reported that responses among patients with lung cancer are seen most often in females who were never smokers, particularly Asian women and those with adenocarcinoma cell type[citation needed].

Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.[3]

The drug's US patent will expire in 2020. [4]. In India, generic pharmaceutical firm Cipla is battling with Roche against the Indian patent for this drug. In April 2009, the Delhi High Court granted a final approval to Cipla to manufacture and sell its generic version of Erlotinib in India. [5] Meanwhile, another generic pharmaceutical firm - Natco is also seeking to manufacture the generic version of Erlotinib in India BUT sell it to patients in Nepal using the TRIPS Agreements' Doha Declaration. [6] [7]

[edit] Administration

Oral tablets

[edit] Side effects

Common side effects include:

  • Rash occurs in the majority of patients. This resembles acne and primarily involves the face and neck. It is self-limited and resolves in the majority of cases, even with continued use. Interestingly, some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed.[8] The Journal of Clinical Oncology reported in 2004 that "cutaneous [skin] rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies."[9] The newsletter Lung Cancer Frontiers reported in its October 2003 issue, "Patients with moderate to severe cutaneous reactions [rashes] have a far better survival, than those with only mild reactions and much better than those with no cutaneous manifestations of drug effects."[10]
  • Diarrhea
  • Loss of appetite
  • Fatigue
  • Rarely, interstitial pneumonitis, which is characterized by cough and increased dyspnea. This may be severe and must be considered among those patients whose breathing acutely worsens.
  • Rarely, ingrown hairs, such as eyelashes
  • It has also been suggested that erlotinib can cause hearing loss.
  • Partial hair loss (by strands, not typically in clumps)

Rare Side Effects:

In spring 2009, the US Food and Drug Administration issued a warning on erlotinib. The FDA reported serious gastrointestinal tract, skin, and ocular disorders in patients taking the drug. In addition, according to a letter released by Genentech and OSI Pharmaceuticals, some people prescribed erlotinib have developed serious or fatal gastrointestinal tract perforations; "bullous, blistering, and exfoliative skin conditions, some fatal; and serious eye problems such as corneal lesions. Some of the cases, including ones which resulted in death, were suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis.[11]

[edit] Resistance to treatment

A key issue with EGFR-directed treatments is that after a period of 8–12 months, the cancer cells become resistant to the treatment, most commonly by recruiting a mutated IGF-1 receptor to act as one of the EGFR partners in the homodimer, so forming a heterodimer.[12] This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538[13] or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541.[14]

[edit] Tarceva studies and availability

In November 2008 a study undertaken by Roche Holding of Switzerland claimed that Tarceva given immediately after chemotherapy may prove to stem the progress of lung cancer. Tarceva blocked the spread of advanced non-small cell lung cancer, researchers found.[15]. However, the report of this study, called SATURN, does not indicate the extent of increase in survival-time.

Tarceva is currently (2009) available for free in Scotland but not in England, as the National Institute for Health and Clinical Excellence (NICE) found it was not "an effective use of NHS resources". Tarceva has been shown to extend the lives of some cancer patients and to improve their quality of life. It is used extensively in Europe and the US.[16]

[edit] Notes

http://www.cancer.gov/clinicaltrials/results/lung-and-erlotinib0604l http://www.roche.com/med-cor-2007-10-22 http://www.roche.com/med-cor-2009-05-30b http://www.cipla.com/whatsnew/news.htm#27apr09 http://www.cipla.com/whatsnew/news.htm#20mar08

[edit] References

  1. ^ Raymond E, Faivre S, Armand J. "Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy". Drugs 60 Suppl 1: 15–23; discussion 41–2. PMID 11129168. 
  2. ^ 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.
  3. ^ Li Z, Xu M, Xing S, Ho W, Ishii T, Li Q, Fu X, Zhao Z (2007). "Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth". J Biol Chem 282 (6): 3428–32. doi:10.1074/jbc.C600277200. PMID 17178722. 
  4. ^ [1][dead link]
  5. ^ http://sify.com/finance/equity/fullstory.php?id=14626687
  6. ^ http://sify.com/finance/equity/fullstory.php?id=14612495
  7. ^ http://www.cipla.com/whatsnew/news.htm#27apr09
  8. ^ Dudek A, Kmak K, Koopmeiners J, Keshtgarpour M (2006). "Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer". Lung Cancer 51 (1): 89–96. doi:10.1016/j.lungcan.2005.09.002. PMID 16290256. 
  9. ^ Román Pérez-Soler, M.D., et al. (2004). "Selected Highlights". Lung Cancer Frontiers 22 (16): 3238–3247. 
  10. ^ Thomas L. Petty, M.D. (2003). "Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer". Journal of Clinical Oncology 1 (17): 3–4. 
  11. ^ http://jama.ama-assn.org/cgi/content/extract/301/24/2542-b
  12. ^ Jones H, Goddard L, Gee J, Hiscox S, Rubini M, Barrow D, Knowlden J, Williams S, Wakeling A, Nicholson R (2004). "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells". Endocr Relat Cancer 11 (4): 793–814. doi:10.1677/erc.1.00799. PMID 15613453.  Free full text
  13. ^ Blum G, Gazit A, Levitzki A (2000). "Substrate competitive inhibitors of IGF-1 receptor kinase". Biochemistry 39 (51): 15705–12. doi:10.1021/bi001516y. PMID 11123895. 
  14. ^ Warshamana-Greene G, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal G (2005). "The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy". Clin Cancer Res 11 (4): 1563–71. doi:10.1158/1078-0432.CCR-04-1544. PMID 15746061.  Free full text
  15. ^ November 2008 - Tarceva may contain lung cancer, study suggests
  16. ^ Daily Mail - October 2007 - Girl of six raises £4,000 for life-saving drugs the NHS won't provide

[edit] External links

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Tyrosine kinase inhibitors ("-nib")
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