Gefitinib

spinqualitylabelsall models Gefitinib, also known as Iressa Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Better Known as: Iressa Marketed By: AstraZeneca & Teva Major Indication: Pancreatic & Small Cell 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 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 and subsequent signaling cascades. Gefitinib inhibits the EGFR tyrosine kinase by binding to the ATP-binding site 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. 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

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