Erlotinib Explained

Verifiedrevid:464189825
Width:250
Tradename:Tarceva
Dailymedid:Erlotinib
Pregnancy Au:C
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:EB02
Legal Au:S4
Legal Au Comment:[2]
Legal Uk:POM
Legal Us:Rx-only
Bioavailability:59%
Protein Bound:95%
Metabolism:Liver (mainly CYP3A4, less CYP1A2)
Elimination Half-Life:36.2 hrs (median)
Excretion:>98% as metabolites, of which >90% via feces, 9% via urine
Iuphar Ligand:4920
Cas Number:183321-74-6
Pubchem:176870
Drugbank:DB00530
Chemspiderid:154044
Unii:J4T82NDH7E
Kegg:D07907
Chebi:114785
Chembl:553
Synonyms:Erlotinib hydrochloride
Iupac Name:
  • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
  • quinazolin-4-amine
C:22
H:23
N:3
O:4
Smiles:COCCOc1cc2c(cc1OCCOC)ncnc2Nc3cccc(c3)C#C
Stdinchi:1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
Stdinchikey:AAKJLRGGTJKAMG-UHFFFAOYSA-N

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

Common side effects include rash, diarrhea, muscle pain, joint pain, and cough.[3] Serious side effects may include lung problems, kidney problems, liver failure, gastrointestinal perforation, stroke, and corneal ulceration. Use in pregnancy may harm the baby. It is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).

Erlotinib was approved for medical use in the United States in 2004.[4] [5] It is on the World Health Organization's List of Essential Medicines.[6]

Medical uses

Lung cancer

Erlotinib in unresectable non-small cell lung cancer when added to chemotherapy improves overall survival by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone.[7] [8] [9] The U.S. Food and Drug Administration (FDA) approved erlotinib for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen.[10]

In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in patients with EGFR mutations.[11] [12] Overall survival, progression-free survival and one-year survival are similar to standard second-line therapy (docetaxel or pemetrexed). Overall response rate is about 50% better than standard second-line chemotherapy.[12] Patients who are non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC are more likely to have EGFR mutations, but mutations can occur in all types of patients. A test for the EGFR mutation has been developed by Genzyme.[13]

Pancreatic cancer

In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

Resistance to treatment

As with other ATP competitive small molecule tyrosine kinase inhibitors, such as imatinib in CML, patients rapidly develop resistance. In the case of erlotinib this typically occurs 8–12 months from the start of treatment. Over 50% of resistance is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue (T790M).[14]

Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3 dependent activation of PI3K.[15] [16]

Side effects

Common

Rare

Interactions

Erlotinib is not a substrate for either of hepatic OATPs (OATP1B1 or OATP1B3).[22] Also, erlotinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.[23]

Erlotinib is mainly metabolized by the liver enzyme CYP3A4. Compounds which induce this enzyme (i.e. stimulate its production), such as St John's wort, can lower erlotinib concentrations, while inhibitors can increase concentrations.[24]

Mechanism

Erlotinib is an epidermal growth factor receptor inhibitor (EGFR inhibitor). The drug follows Iressa (gefitinib), which was the first drug of this type. 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.[25] For the signal to be transmitted, two EGFR molecules need to come together to form a homodimer. These then use the molecule of ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. When erlotinib binds to EGFR, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.

Society and culture

It is marketed in the United States by Genentech and OSI Pharmaceuticals[26] and elsewhere by Roche.[27]

The drug's U.S. patent expired in 2020.[28] In May 2012, the US District Court of Delaware passed an order in favor of OSI Pharmaceutical LLC against Mylan Pharmaceuticals upholding the validity of the patent for Erlotinib. In India, generic pharmaceutical firm Cipla is battling with Roche against the Indian patent for this drug.[29] [30]

External links

Notes and References

  1. Web site: Erlotinib (Tarceva) Use During Pregnancy . Drugs.com . 1 November 2019 . 23 December 2019 . 12 November 2019 . https://web.archive.org/web/20191112154642/https://www.drugs.com/pregnancy/erlotinib.html . live .
  2. Web site: Tarceva (Erlotinib hydrochloride) . Australian Product Information . Roche Products Pty Limited . 31 August 2022 .
  3. Web site: Tarceva- erlotinib hydrochloride tablet . . 12 December 2018 . 23 December 2019 . 6 August 2020 . https://web.archive.org/web/20200806135458/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20 . live .
  4. Web site: Drug Approval Package: Tarceva (Erlotinib) NDA #021743 . U.S. Food and Drug Administration (FDA) . 28 March 2005 . 23 December 2019 . 23 December 2019 . https://web.archive.org/web/20191223215422/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva.cfm . live .
  5. Web site: Erlotinib Monograph for Professionals . Drugs.com . 12 November 2019 . 24 December 2019 . https://web.archive.org/web/20191224052912/https://www.drugs.com/monograph/erlotinib.html . live .
  6. Book: World Health Organization model list of essential medicines: 21st list 2019 . 2019. 10665/325771 . World Health Organization . Organization . World Health .
  7. Web site: 2009 - SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. . 18 December 2010 . 22 December 2010 . https://web.archive.org/web/20101222034936/http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=32756 . dead .
  8. Web site: April 2010 - Tarceva Indication Announcement Letter . 18 December 2010 . 16 July 2011 . https://web.archive.org/web/20110716192656/http://www.tarceva.com/docs/Indication_Announcement_Letter.pdf . live .
  9. Gijtenbeek RG, van der Noort V, Aerts JG, Staal-van den Brekel JA, Smit EF, Krouwels FH, Wilschut FA, Hiltermann TJ, Timens W, Schuuring E, Janssen JD, Goosens M, van den Berg PM, de Langen AJ, Stigt JA, van den Borne BE, Groen HJ, van Geffen WH, van der Wekken AJ . Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer . ERJ Open Research . 8 . 4 . 00239–2022 . October 2022 . 36267895 . 9574558 . 10.1183/23120541.00239-2022 .
  10. Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R . FDA drug approval summary: erlotinib (Tarceva) tablets . The Oncologist . 10 . 7 . 461–466 . August 2005 . 16079312 . 10.1634/theoncologist.10-7-461 . 10218263 . free .
  11. Kobayashi K, Hagiwara K . Epidermal growth factor receptor (EGFR) mutation and personalized therapy in advanced nonsmall cell lung cancer (NSCLC) . Targeted Oncology . 8 . 1 . 27–33 . March 2013 . 23361373 . 3591525 . 10.1007/s11523-013-0258-9 .
  12. Qi WX, Shen Z, Lin F, Sun YJ, Min DL, Tang LN, He AN, Yao Y . Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis . Asian Pacific Journal of Cancer Prevention . 13 . 10 . 5177–5182 . 2012 . 23244131 . 10.7314/APJCP.2012.13.10.5177 . free .
  13. Roche obtains license for EGFR lung cancer assays and will develop Tarceva companion diagnostic test. Roche. 10 January 2020. 24 February 2022. https://web.archive.org/web/20220224044600/https://www.roche.com/investors/updates/inv-update-2010-11-23. live.
  14. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W . Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors . Clinical Cancer Research . 12 . 21 . 6494–6501 . November 2006 . 17085664 . 10.1158/1078-0432.CCR-06-1570 . free .
  15. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA . MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling . Science . 316 . 5827 . 1039–1043 . May 2007 . 17463250 . 10.1126/science.1141478 . 23254145 . 2007Sci...316.1039E . free .
  16. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W . MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib . Proceedings of the National Academy of Sciences of the United States of America . 104 . 52 . 20932–20937 . December 2007 . 18093943 . 2409244 . 10.1073/pnas.0710370104 . free . 2007PNAS..10420932B .
  17. Dudek AZ, Kmak KL, Koopmeiners J, Keshtgarpour M . 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 . January 2006 . 16290256 . 10.1016/j.lungcan.2005.09.002 .
  18. Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabárbara P, Bonomi P . Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer . Journal of Clinical Oncology . 22 . 16 . 3238–3247 . August 2004 . 15310767 . 10.1200/JCO.2004.11.057 . free .
  19. Petty TL . Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer . Journal of Clinical Oncology . 1 . 17 . 3–4 . 2003 .
  20. Li X, Kamenecka TM, Cameron MD . Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile . Drug Metabolism and Disposition . 38 . 7 . 1238–1245 . July 2010 . 20382753 . 3202369 . 10.1124/dmd.109.030361 .
  21. Ren S, Li Y, Li W, Zhao Z, Jin C, Zhang D . Fatal asymmetric interstitial lung disease after erlotinib for lung cancer . Respiration; International Review of Thoracic Diseases . 84 . 5 . 431–435 . 2012 . 22889962 . 10.1159/000339508 . free .
  22. Khurana V, Minocha M, Pal D, Mitra AK . Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors . Drug Metabolism and Drug Interactions . 29 . 3 . 179–190 . March 2014 . 24643910 . 4407685 . 10.1515/dmdi-2013-0062 .
  23. Khurana V, Minocha M, Pal D, Mitra AK . Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors . Drug Metabolism and Drug Interactions . 29 . 4 . 249–259 . May 2014 . 24807167 . 4407688 . 10.1515/dmdi-2014-0014 .
  24. Book: Austria-Codex. Haberfeld, H. Österreichischer Apothekerverlag. Vienna. 2010. 2010/2011. de.
  25. Raymond E, Faivre S, Armand JP . Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy . Drugs . 60 . Suppl 1 . 15–23; discussion 41–2 . 2000 . 11129168 . 10.2165/00003495-200060001-00002 . 10555942 . free .
  26. Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415 . Drugs in R&D . 4 . 4 . 243–248 . 2003 . 12848590 . 10.2165/00126839-200304040-00006 . Adis International Ltd .
  27. Web site: FDA Approves Roche Test as CDx for Tarceva for Treating Certain NSCLC Patients. GenomeWeb. 15 May 2013. en-us. 10 January 2020. 6 September 2019. https://web.archive.org/web/20190906203021/https://www.genomeweb.com/diagnostics/fda-approves-roche-test-cdx-tarceva-treating-certain-nsclc-patients. live.
  28. Web site: Erlotinib - Generic Drug Details . https://web.archive.org/web/20160428083918/http://drugpatentwatch.com/p/ingredient/erlotinib . 28 April 2016 . DrugPatentWatch.com .
  29. Web site: Roche and India's Glenmark reach truce over generic Tarceva . GaBI Online . 22 January 2016 . https://web.archive.org/web/20191224075230/http://www.gabionline.net/Generics/News/Roche-and-India-s-Glenmark-reach-truce-over-generic-Tarceva . 24 December 2019 . live . 23 December 2019.
  30. News: Cancer drug: Supreme Court allows Cipla to withdraw appeal against Roche . The Economic Times . 16 June 2017 . https://web.archive.org/web/20191224075759/https://economictimes.indiatimes.com/cancer-drug-supreme-court-allows-cipla-to-withdraw-appeal-against-roche/articleshow/59176743.cms . 24 December 2019 . live . 23 December 2019.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Erlotinib".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.