afatinib

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Ligands
afatinib

GtoPdb Ligand ID: 5667

Synonyms: BIBW2992 | Gilotrif®

afatinib is an approved drug (EMA & FDA (2013))

Comment: Afatinib is a second-generation, irreversible, covalently-bound EGFR tyrosine kinase inhibitor. It potently and selectively inhibits EGFR and Erbb2 [3,5,7]. Although afatinib demonstrates improved activity against the gatekeeper EGFR T790M resistance mutation, it is equally potent against the wild-type receptor, leading to dose-limiting toxicities and a narrow safety window [8]. Third generation, wild-type sparing inhibitors such as nazartinib are in development to circumvent this problem [4].

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: afatinib

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	7
Hydrogen bond donors	2
Rotatable bonds	9
Topological polar surface area	88.61
Molecular weight	485.16
XLogP	3.1
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	CN(CC=CC(=O)Nc1cc2c(ncnc2cc1OC1COCC1)Nc1ccc(c(c1)Cl)F)C
Isomeric SMILES	CN(C/C=C/C(=O)Nc1cc2c(ncnc2cc1O[C@@H]1COCC1)Nc1ccc(c(c1)Cl)F)C
InChI	InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1
InChI Key	ULXXDDBFHOBEHA-CWDCEQMOSA-N

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No information available.

Summary of Clinical Use
Afatinib is an irreversible kinase inhibitor approved for first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have activating mutations in the epidermal growth factor receptor (EGFR). Such mutations must be confirmed by an FDA-approved test. Marketed formulations contain afatinib dimaleate (PubChem CID 15606394). In April 2016, the US FDA expanded approval to include monotherapy treatment of patients with advanced squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy. January 2018, saw FDA approval broadened to include use as first-line treatment for metastatic NSCLC in tumors that have non-resistant EGFR mutations as detected by an FDA-approved test.

Summary of Clinical Use

Afatinib is an irreversible kinase inhibitor approved for first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have activating mutations in the epidermal growth factor receptor (EGFR). Such mutations must be confirmed by an FDA-approved test.
Marketed formulations contain afatinib dimaleate (PubChem CID 15606394).

In April 2016, the US FDA expanded approval to include monotherapy treatment of patients with advanced squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy.
January 2018, saw FDA approval broadened to include use as first-line treatment for metastatic NSCLC in tumors that have non-resistant EGFR mutations as detected by an FDA-approved test.

Mechanism Of Action and Pharmacodynamic Effects
Afatinib irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 all of which have been reported to be involved in pathways that help tumour cells to grow, migrate and metastasise. The resulting downregulation of ErbB signalling and inhibition of tumour cell proliferation increases progression free survival time in suitable patients (compared to chemotherepy).

Mechanism Of Action and Pharmacodynamic Effects

Afatinib irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 all of which have been reported to be involved in pathways that help tumour cells to grow, migrate and metastasise. The resulting downregulation of ErbB signalling and inhibition of tumour cell proliferation increases progression free survival time in suitable patients (compared to chemotherepy).

Pharmacokinetics
Absorption/Distribution
T_max is 2-5 h after oral dosing of afatinib in tablet form. Afatinib is best administered in the fasted state. Steady-state plasma concentrations are attained within 8 days. Maximum concentration (C_max) and AUC show high inter-patient variability. In vitro binding of afatinib to human plasma proteins is approximately 95%, but the absolute bioavailibility of the drug in humans is unknown.
Biotransformation/Metabolism
Enzymatic meatbolism of afatinib is minimal. The major circulating metabolites are covalently linked protein adducts.
Elimination
Elimination half life is 37 hours, with 85% eliminated in feces and 4% excreted in urine. 88% of the excreted drug is unmetabolized.
Population pharmacokinetics
There are no clinically relevant differences in exposure to afatinib associated with age, gender or race.
Organ function impairment
Dose adjustment may be required in patients with mild or moderate renal function impairment. Patients with severe renal impairment have not been studued. Mild and moderate hepatic failure has no influence on afatinib exposure. Patients with severe hapatic failure have not been studied. No large changes in the mean QTc interval (>20 ms) are reported following multiple daily oral doses of afatinib.

Pharmacokinetics

Absorption/Distribution

T_max is 2-5 h after oral dosing of afatinib in tablet form. Afatinib is best administered in the fasted state. Steady-state plasma concentrations are attained within 8 days. Maximum concentration (C_max) and AUC show high inter-patient variability. In vitro binding of afatinib to human plasma proteins is approximately 95%, but the absolute bioavailibility of the drug in humans is unknown.

Biotransformation/Metabolism

Enzymatic meatbolism of afatinib is minimal. The major circulating metabolites are covalently linked protein adducts.

Elimination

Elimination half life is 37 hours, with 85% eliminated in feces and 4% excreted in urine. 88% of the excreted drug is unmetabolized.

Population pharmacokinetics

There are no clinically relevant differences in exposure to afatinib associated with age, gender or race.

Organ function impairment

Dose adjustment may be required in patients with mild or moderate renal function impairment. Patients with severe renal impairment have not been studued. Mild and moderate hepatic failure has no influence on afatinib exposure. Patients with severe hapatic failure have not been studied. No large changes in the mean QTc interval (>20 ms) are reported following multiple daily oral doses of afatinib.