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Imatinib

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Imatinib, also known as Gleevec (2hyy)

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Better Known as: Gleevec

  • Marketed By: Novartis
  • Major Indication: Chronic Myelogenous 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

Mechanism of Action

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

[2]

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

References

  1. ↑ A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, November 2, 2009
  2. ↑ 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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