Lapatinib

spinqualitylabelsall models Lapatinib, also known as Tykerb (3bbt) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Better Known as: Tykerb Marketed By: GlaxoSmithKline Major Indication: Breast Cancer Drug Class: EGFR Inhibitor Date of FDA Approval (Expiration): 2007 (2017) 2009 Sales (Projected Peak): $150 Million ($4.5 Billion) Importance: It is one of the newest treatments for cancer. Complaints over the high cost ($22,000) for a treatment course which only prolongs survival in breast cancer patients by less than 2 months. It is particularly effective against HER2-positive breast cancer. 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, and are often mutated. 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. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins. Erlotinib inhibits the EGFR tyrosine kinase by binding to the ATP-binding site located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. 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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