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Afatinib (BIBW2992)

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Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications.It is taken by mouth.

Product Description

Basic Characteristics

Product Name Afatinib (BIBW2992)
CAS Number 850140-73-7
Molecular Formula C32H33ClFN5O11
Formula Weight 718.09
Synonyms 850140-73-7;

BIBW-2992;

BIBW 2992;

BIBW2992. Afatinib dimaleate;

Appearance Light yellow powder
Storage and Handling Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).

 

Afatinib Description

Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications.It is taken by mouth.It is mainly used to treat cases of NSCLC that harbour mutations in the epidermal growth factor receptor (EGFR) gene.

Afatinib (BIBW2992), an irreversible inhibitor of the ErbB family of tyrosine kinases, was shown to suppress EGF-induced phosphorylation of EGFR and cell proliferation in a variety of EGFR-overexpressing and HER2-expressing cell lines such as A431, NIH-3T3-HER2, NCI-N87 and BT-474.

The component has also been used extensively in various animal models to study the role of EGFR/HER2. Oral administration of afatinib inhibited cancer cell growth and survival and suppress the tumor regression in xenograft and transgenic lung cancer models. In addition, afatinib is identified as EGFR blocker which was approved for the treatment of patients with EGFR-mutated nonsmall cell lung cancer.

 

Afatinib Mechanism of Action

Like lapatinib and neratinib, afatinib is a protein kinase inhibitor 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 tyrosine-kinase inhibitors (TKIs) like erlotinib or gefitinib, but also against less common mutations which are resistant to these drugs.

However, it is not active against the T790M mutation which generally requires third generation drugs like osimertinib. Because of its additional activity against Her2, it is being investigated for breast cancer as well as other EGFR and Her2 driven cancers.

 

Afatinib Application

Afatinib is an orally bioavailable anilino-quinazoline derivative and inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity.

Afatinib also is an orally bioavailable dual receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. EGFR/HER2 tyrosine kinase inhibitor BIBW 2992 irreversibly binds to and inhibits human epidermal growth factor receptors 1 and 2 (EGFR-1; HER2), which may result in the inhibition of tumor growth and angiogenesis. EGFR/HER2 are RTKs that belong to the EGFR superfamily; both play major roles in tumor cell proliferation and tumor vascularization and are overexpressed in many cancer cell types.

Afatinib is 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. It acts as an angiokinase inhibitor.

 

Afatinib Side Effects & Warning

The following side effects are common (occurring in greater than 30%) for patients taking afatinib:

▪ Diarrhea

▪ Acneiform eruption (group of skin conditions resembling acne)

▪ Mouth sores

▪ Paronychia (infection of nails)

▪ Dry mouth

 

These are less common side effects (occurring in 10-29%) for patients receiving afatinib:

▪ Decreased appetite

▪ Itching

▪ Weight loss

▪ Nose bleeds

▪ Cystitis (bladder infection)

▪ Cheilitis (inflammation of the lips)

▪ Fever

▪ Hypokalemia (low potassium)

▪ Conjunctivitis (pink eye)

▪ Rhinorrhea (runny nose)

▪ Elevated liver enzymes

Not all side effects are listed above. Some that are rare (occurring in less than about 10 percent of patients) are not listed here. Always inform your health care provider if you experience any unusual symptoms.

 

Important things to remember about the side effects of afatinib:

▪ Most people will not experience all of the afatinib side effects listed.

▪ Afatinib side effects are often predictable in terms of their onset, duration, and severity.

▪ Afatinib side effects are almost always reversible and will go away after therapy is complete.

▪ Afatinib side effects may be quite manageable. There are many options to minimize or prevent the side effects of afatinib.

 

Reference

[1] Prim N, Fore M, Mennecier B. [Afatinib (BIBW 2992).]. Rev Pneumol Clin. 2014 May 27. pii: S0761-8417(14)00047-9. doi: 10.1016/j.pneumo.2014.03.002. [Epub ahead of print] Review. French. PubMed PMID: 24878189.

[2] D’Arcangelo M, Hirsch FR. Clinical and comparative utility of afatinib in non-small cell lung cancer. Biologics. 2014 Apr 23;8:183-92. doi: 10.2147/BTT.S40567. eCollection 2014. Review. PubMed PMID: 24790411; PubMed Central PMCID: PMC4003149.

[3] Bowles DW, Weickhardt A, Jimeno A. Afatinib for the treatment of patients with EGFR-positive non-small cell lung cancer. Drugs Today (Barc). 2013 Sep;49(9):523-35. doi: 10.1358/dot.2013.49.9.2016610. Review. PubMed PMID: 24086949.

[4] Köhler J, Schuler M. Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation-positive lung adenocarcinoma: a review. Onkologie. 2013;36(9):510-8. doi: 10.1159/000354627. Epub 2013 Aug 19. Review. PubMed PMID: 24051929.

[5] Yap TA, Popat S. The role of afatinib in the management of non-small cell lung carcinoma. Expert Opin Drug Metab Toxicol. 2013 Nov;9(11):1529-39. doi: 10.1517/17425255.2013.832755. Epub 2013 Aug 28. Review. PubMed PMID: 23985030.

[6] Dungo RT, Keating GM. Afatinib: first global approval. Drugs. 2013 Sep;73(13):1503-15. doi: 10.1007/s40265-013-0111-6. Review. PubMed PMID: 23982599.

[7] Minkovsky N, Berezov A (December 2008). “BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors”. Current Opinion in Investigational Drugs. 9 (12): 1336–46. PMID 19037840

[8] Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. (August 2008). “BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models”. Oncogene. 27 (34): 4702–11. doi:10.1038/onc.2008.109. PMC 2748240. PMID 18408761.