Imatinib

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Revision as of 13:28, 10 December 2010

Marketed By: Novartis
Major Indication: Leukemia and Gastrointestinal Stromal Tumors
Drug Class: Receptor Tyrosine Kinase (Especially PDGFR, Abl & KIT) Inhibitor
Date of FDA Approval (Expiration): 2001 (2015)
2009 Global Sales: $3.9 Billion
Importance: It is one of the best selling cancer drugs of all time. It was the drug to be approved from the tyrosine kinase inhibitor class of drugs. It is very specific receptor tyrosine kinase (RTK) inhibitor, binding to Abl, PDGFR and KIT with far greater specificity than other RTKs, helping explain its relatively low impact side effect profile. Although now considered hyperbole, TIME magazine declared that Gleevec was "converting a fatal cancer into a manageable chronic condition." Has generated significant controversy due to its nearly $65,000 per year cost at a time when global health care budgets are being stretched thin.^[1]
See Pharmaceutical Drugs for more information about other drugs and disorders

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)
T_max (hr)	8	8.3	2.0	5.4	4	3.7	3.0	1.0
C_max (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
T_1/2 (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

↑ A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, November 2, 2009
↑ Cowan-Jacob SW, Fendrich G, Floersheimer A, Furet P, Liebetanz J, Rummel G, Rheinberger P, Centeleghe M, Fabbro D, Manley PW. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):80-93. Epub 2006, Dec 13. PMID:17164530 doi:http://dx.doi.org/10.1107/S0907444906047287

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 ===Mechanism of Action===
-[[EGFR|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer|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_Replication|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> 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.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> 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.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>
+<ref>doi: 10.1107/S0907444906047287</ref>
 ===Pharmacokinetics===