Erlotinib

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Erlotinib
Clinical data
Trade namesTarceva
Other namesErlotinib hydrochloride
AHFS/Drugs.comMonograph
MedlinePlusa605008
License data
Pregnancy
category
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability59%
Protein binding95%
MetabolismLiver (mainly CYP3A4, less CYP1A2)
Elimination half-life36.2 hrs (median)
Excretion>98% as metabolites, of which >90% via feces, 9% via urine
Identifiers
    • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
    • quinazolin-4-amine
JSmol)
  • COCCOc1cc2c(cc1OCCOC)ncnc2Nc3cccc(c3)C#C
  • InChI=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) checkY
  • Key:AAKJLRGGTJKAMG-UHFFFAOYSA-N checkY
  (verify)

Erlotinib, sold under the brand name Tarceva among others, is a

by mouth.[4]

Common side effects include rash, diarrhea, muscle pain, joint pain, and cough.

corneal ulceration.[4] Use in pregnancy may harm the baby.[4] It is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).[4]

Erlotinib was approved for medical use in the United States in 2004.

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

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.[14]

Resistance to treatment

Erlotinib bound to ErbB1 at 2.6A resolution; surface colour indicates hydrophobicity.

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).[15]

Approximately 20% of drug resistance is caused by amplification of the

PI3K.[16][17]

Side effects

Common

  • 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. Some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed.[18] 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."[19] 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."[20]
  • Diarrhea
  • Loss of appetite
  • Fatigue[9]
  • Partial hair loss (by strands, not typically in clumps)

Rare

Interactions

Erlotinib is not a substrate for either of hepatic

OATPs (OATP1B1 or OATP1B3).[23] Also, erlotinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.[24]

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.[25]

Mechanism

Erlotinib is an epidermal growth factor receptor inhibitor (

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

Roche.[28]

The drug's U.S. patent expired in 2020.[29] 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.[citation needed] In India, generic pharmaceutical firm Cipla is battling[when?] with Roche against the Indian patent for this drug.[30][31]

References

  1. ^ "Erlotinib (Tarceva) Use During Pregnancy". Drugs.com. 1 November 2019. Archived from the original on 12 November 2019. Retrieved 23 December 2019.
  2. ^ a b "Tarceva (Erlotinib hydrochloride)". Roche Products Pty Limited. Australian Product Information. 31 August 2022.
  3. ^ a b c d "Tarceva- erlotinib hydrochloride tablet". DailyMed. 12 December 2018. Archived from the original on 6 August 2020. Retrieved 23 December 2019.
  4. ^ a b c d e f g h "Erlotinib Monograph for Professionals". Drugs.com. Archived from the original on 24 December 2019. Retrieved 12 November 2019.
  5. ^ "Drug Approval Package: Tarceva (Erlotinib) NDA #021743". U.S. Food and Drug Administration (FDA). 28 March 2005. Archived from the original on 23 December 2019. Retrieved 23 December 2019.
  6. hdl:10665/325771
    .
  7. ^ "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". Archived from the original on 22 December 2010. Retrieved 18 December 2010.
  8. ^ "April 2010 - Tarceva Indication Announcement Letter" (PDF). Archived (PDF) from the original on 16 July 2011. Retrieved 18 December 2010.
  9. ^
    PMID 36267895
    .
  10. S2CID 10218263
    .
  11. PMID 23361373
    .
  12. ^
    PMID 23244131
    .
  13. ^ "Roche obtains license for EGFR lung cancer assays and will develop Tarceva companion diagnostic test". Roche (Press release). Archived from the original on 24 February 2022. Retrieved 10 January 2020.
  14. ^ Takimoto CH, Calvo E (15 April 2009), Principles of Oncologic Pharmacotherapy, archived from the original on 15 May 2009, retrieved 18 June 2009
  15. PMID 17085664
    .
  16. S2CID 23254145
    .
  17. PMID 18093943
    .
  18. PMID 16290256
    .
  19. PMID 15310767
    .
  20. ^ Petty TL (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.
  21. PMID 20382753
    .
  22. PMID 22889962
    .
  23. PMID 24643910
    .
  24. PMID 24807167
    .
  25. ^ Haberfeld, H, ed. (2010). Austria-Codex (in German) (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
  26. S2CID 10555942
    .
  27. PMID 12848590
    .
  28. ^ "FDA Approves Roche Test as CDx for Tarceva for Treating Certain NSCLC Patients". GenomeWeb. 15 May 2013. Archived from the original on 6 September 2019. Retrieved 10 January 2020.
  29. ^ "Erlotinib - Generic Drug Details". DrugPatentWatch.com. Archived from the original on 28 April 2016.
  30. ^ "Roche and India's Glenmark reach truce over generic Tarceva". GaBI Online. 22 January 2016. Archived from the original on 24 December 2019. Retrieved 23 December 2019.
  31. ^ "Cancer drug: Supreme Court allows Cipla to withdraw appeal against Roche". The Economic Times. 16 June 2017. Archived from the original on 24 December 2019. Retrieved 23 December 2019.

External links

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