Gefitinib
From Proteopedia
|
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
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
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 EGFR tyrosine kinase domain 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. This signal transduction ultimately leads to activation of the MAPK, Akt and JNK pathways, in addition
Gefitinib inhibits the EGFR tyrosine kinase by binding to the ATP-Binding site located within the kinase domain. Unable to bind ATP, EGFR is unable to
Pharmacokinetics
| EGFR Inhibitor Pharmacokinetics Comparison at Equivalent Dosages [1][2][3] | |||
|---|---|---|---|
| Parameter | Erlotinib (Tarceva) | Gefitinib (Iressa) | Lapatinib (Tykerb) |
| Tmax (hr) | 2.0 | 5.4 | 4 |
| Cmax (ng/ml) | 69.6 | 130 | 115 |
| Bioavailability (%) | 99 | 59 | Variable |
| Protein Binding (%) | 93 | 90 | 99 |
| T1/2 (hr) | 9.4 | 26.9 | 9.6 |
| AUC (ng/ml/hr) | 20577 | 3850 | 1429 |
| Typical Dosage (mg) | 150 | 250 | 100 |
| Metabolism | Hepatic - (CYP3A4) | Hepatic - (CYP3A4) | Hepatic - (CYP3A4) |
References
- ↑ Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. PMID:16609030 doi:10.1158/1078-0432.CCR-05-2235
- ↑ Bergman E, Forsell P, Persson EM, Knutson L, Dickinson P, Smith R, Swaisland H, Farmer MR, Cantarini MV, Lennernas H. Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors. Int J Pharm. 2007 Aug 16;341(1-2):134-42. Epub 2007 Apr 6. PMID:17482782 doi:10.1016/j.ijpharm.2007.04.002
- ↑ D. Smith et al. Br J Clin Pharmacol. 2009 April; 67(4): 421–426.
