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)[1]
- 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.[2][3] 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.[4][5]
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
|
- ↑ https://money.cnn.com/2006/06/03/news/companies/glaxo_breastcancer/index.htm
- ↑ 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
- ↑ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980 doi:10.1158/0008-5472.CAN-04-1168
