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The SARfaris: GPCR, Kinase, ADME

Sunday, 14 July 2013

New Drug Approvals 2013 - Pt. XI - Afatinib (GilotrifTM)

ATC code: L01XE13


On July 12th 2013 the FDA approved GilotrifTM (USAN afatinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) carrying EGFR exon 19 deletions or exon 21 (L858R) mutation. It is a covalent, irreversible inhibitor of EGFR, ERBB2 and ERBB3.

Non small cell lung cancer (NCLS) (CRUK NCLS; PDQ NCLS) accounts for 78% of lung cancer incidences in the UK and is typically resistant to chemotherapy. In clinical studies, afatinib increased the mean Progression Free Survival to 11.1 months from 6.9 months (compared to standard of care Pemetrexed/Cisplatin). Furthermore, response to treatment was observed in tumors harboring several EGFR mutant species although the duration of response varied from 6.9 months to 16.5 months depending on the mutation .

Afatinib covalently binds to the kinase domains of EGFR (ErbB1, Uniprot: P00533; canSAR: EGFR”), HER2 (ErbB2, Uniprot:P04626; canSAR: ERBB2), and HER4 (ErbB4, Uniprot:Q15303; canSAR: ERBB4)) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. The structure of afatinib bound to EGFR is shown (PDB=4G5J).

GilotrifTM tablets contain the dimaleate salt of afatinib. Afatinib (research code: BIBW-2992; ChEMBL id: CHEMBL1173655; SMILES:CN(C)C\C=C\C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]4CCOC4;) has a molecular weight of 485.9 and an AlogP of 3.92. The elimination half-life of afatinib is 37 hours after repeat dosing.

GilotrifTM is produced by Boehringer-Ingelheim

Prescribing information is here.

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