Better Known as: Iressa
- Marketed By: AstraZeneca & Teva
- Major Indication: Pancreatic & Small Cel Lung Cancer
- Drug Class: EGFR Inhibitor
- Date of FDA Approval (Expiration): 2003 (2013)
- 2009 Sales: $268 Million
- Importance: It is the first selective inhibitor of Epidermal Growth Factor Receptors approved by the FDA
- See Pharmaceutical Drugs for more information about other drugs and disorders
Mechanism of Action
Epidermal Growth Factor Receptors are overexpressed in many types of human carcinomas including lung, pancreatic, and breast cancer. This overexpression leads to excessive activation of the anti-apoptotic Ras signalling cascade, resulting in uncontrolled DNA synthesis and cell proliferation. Studies have revealed that the is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. It is these phosphorylated tyrosine residues which elicit downstream activation of other signaling proteins and subsequent signaling cascades.[1][2] Gefitinib inhibits the EGFR tyrosine kinase by located within the kinase domain. Residues Lys 745, Leu 788, Ala 743, Thr 790, Gln 791, Met 193, Pro 794, Gly 796, Asp 800, Ser 719, Glu 762, & Met 766 tightly bind the inhibitor. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.[3]
Pharmacokinetics
| Tyrosine Kinase Inhibitor Pharmacokinetics
|
|
|
VEGFR & KIT Inhibitors
|
EGFR Inhibitors
|
BCR-Abl Inhibitor
|
| Parameter
|
Sunitinib
(Sutent)
|
Sorafenib
(Nexavar)
|
Erlotinib
(Tarceva)
|
Gefitinib
(Iressa)
|
Lapatinib
(Tykerb)
|
Imatinib
(Gleevec)
|
Nilotinib
(Tasigna)
|
Dasatinib
(Sprycel)
|
| Tmax (hr)
|
8
|
8.3
|
2.0
|
5.4
|
4
|
3.7
|
3.0
|
1.0
|
| Cmax (ng/ml)
|
24.6
|
460
|
69.6
|
130
|
115
|
2070
|
411
|
124
|
| Bioavailability (%)
|
Variable
|
29-49
|
99
|
59
|
Variable
|
98
|
30
|
20
|
| Protein Binding (%)
|
95
|
99
|
93
|
90
|
99
|
95
|
98
|
96
|
| T1/2 (hr)
|
83
|
29
|
9.4
|
26.9
|
9.6
|
26.6
|
16.0
|
3.3
|
| AUC (ng/ml/hr)
|
1921
|
11040
|
20577
|
3850
|
1429
|
4760
|
10052
|
461
|
| Dosage (mg)
|
50
|
50
|
150
|
250
|
100
|
400
|
200
|
200
|
| Metabolism
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
Hepatic (CYP3A4)
|
For Pharmacokinetic Data References, see: References
|
References
- ↑ Downward J, Parker P, Waterfield MD. Autophosphorylation sites on the epidermal growth factor receptor. Nature. 1984 Oct 4-10;311(5985):483-5. PMID:6090945
- ↑ Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;1:2005.0010. Epub 2005 May 25. PMID:16729045 doi:10.1038/msb4100014
- ↑ Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163-7. Epub 2004 Jul 29. PMID:15284455 doi:10.1126/science.1101637