Afatinib

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Afatinib
Afatinib2DACS.svg
Systematic (IUPAC) name
N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide
Clinical data
Trade names Gilotrif, Giotrif
AHFS/Drugs.com Multum Consumer Information
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (AU) D (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 92%[1]
Protein binding 95%
Metabolism CYP not involved
Half-life 37 hours
Excretion Faeces (85%), urine (4%)
Identifiers
CAS number 439081-18-2 N
ATC code L01XE13
PubChem CID 10184653
ChemSpider 8360155 YesY
UNII 41UD74L59M YesY
ChEBI CHEBI:61390 YesY
ChEMBL CHEMBL1173655 YesY
Synonyms BIBW 2992
Chemical data
Formula C24H25ClFN5O3 
Mol. mass 485.937 g/mol
 N (what is this?)  (verify)

Afatinib[2] (INN; trade name Gilotrif in the US and Giotrif in Europe, previously Tomtovok and Tovok[3]) is a drug approved in much of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim.[4][5][6] It acts as an angiokinase inhibitor.

Medical uses[edit]

It has received regulatory approval for use as a treatment for non-small cell lung cancer,[7][8][9][10] although there is emerging evidence to support its use in other cancers such as breast cancer.[11]

In October 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug.[12] Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival.[13] In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.[14]

Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib.[11] Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.[15]

Adverse effects[edit]

Adverse effects by frequency:[7][8][9][1][10]


Very common (>10% frequency):

Common (1-10% frequency):

Uncommon (0.1-1% frequency):


Mechanism of action[edit]

Like lapatinib and neratinib, afatinib is a tyrosine kinase inhibitor (TKI) that also irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation TKIs like erlotinib or gefitinib, but also against those not sensitive to these standard therapies.[citation needed] Because of its additional activity against Her2, it is being investigated for breast cancer as well as other EGFR and Her2 driven cancers.[5]

Afatinib covalently binds to cysteine number 797 of the epidermal growth factor receptor (EGFR) via a Michael addition (IC50 = 0.5 nM).[16]

References[edit]

  1. ^ a b "Gilotrif (afatinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 January 2014. 
  2. ^ "Afatinib (BIBW 2992) triples progression free survival in phase III study in lung cancer patients". World Pharma News. 12 October 2010. 
  3. ^ "Afatinib (BIBW-2992, Tomtovok) wins a battle (PFS) but loses the war (OS) for EGFR TKI-sensitive patients". GRACE. 18 October 2010. 
  4. ^ H. Spreitzer (May 13, 2008). "Neue Wirkstoffe - Tovok". Österreichische Apothekerzeitung (in German) (10/2008): 498. 
  5. ^ a b Minkovsky N, Berezov A (December 2008). "BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors". Curr Opin Investig Drugs 9 (12): 1336–46. PMID 19037840. 
  6. ^ "Afatinib". US Food and Drug Administration. 12 July 2013. 
  7. ^ a b "GILOTRIF (afatinib) tablet, film coated [Boehringer Ingelheim Pharmaceuticals, Inc.]". DailyMed. Boehringer Ingelheim Pharmaceuticals, Inc. November 2013. Retrieved 28 January 2014. 
  8. ^ a b "GIOTRIF® Afatinib (as afatinib dimaleate)" (PDF). TGA eBusiness Services. Boehringer Ingelheim Pty Limited. 7 November 2013. Retrieved 28 January 2014. 
  9. ^ a b "Giotrif 20 mg film-coated tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Boehringer Ingelheim Limited. 20 January 2014. Retrieved 28 January 2014. 
  10. ^ a b "Giotrif : EPAR -Product Information" (PDF). European Medicines Agency. Boehringer Ingelheim International GmbH. 16 October 2013. Retrieved 28 January 2014. 
  11. ^ a b Lin, Nancy U.; Winer, Eric P.; Wheatley, Duncan; Carey, Lisa A.; Houston, Stephen; Mendelson, David; Munster, Pamela; Frakes, Laurie et al. (2012). "A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab". Breast Cancer Research and Treatment 133 (3): 1057–65. doi:10.1007/s10549-012-2003-y. PMC 3387495. PMID 22418700. 
  12. ^ ClinicalTrials.gov NCT01085136 LUX-Lung 5: BIBW 2992 Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following BIBW 2992 Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib
  13. ^ "Afatinib (BIBW 2992*) Triples Progression Free Survival in Phase III Study in Lung Cancer Patients". BusinessWire. 11 October 2010. 
  14. ^ Miller, VA; Hirsh, V; Cadranel, J; Chen, YM; Park, K; Kim, SW; Zhou, C; Su, WC et al. (2012). "Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial". The lancet oncology 13 (5): 528–38. doi:10.1016/S1470-2045(12)70087-6. PMID 22452896. 
  15. ^ Schuler, M; Awada, A; Harter, P; Canon, JL; Possinger, K; Schmidt, M; De Grève, J; Neven, P et al. (2012). "A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer". Breast cancer research and treatment 134 (3): 1149–59. doi:10.1007/s10549-012-2126-1. PMC 3409367. PMID 22763464. 
  16. ^ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (German)