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, BCR-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. 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

Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell (HSC). Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding and stabilizing the inactive conformation of BCR-Abl, in which the well known "DFG triad" is in the "out" conformation. In the DFG out conformation the residues surrounding Tyr 393 disrupt the ATP binding site, inhibiting Abl's kinase activity. A critically important residue, Thr 315, is known as the gatekeeper residue. In the inactive DFG out conformation, Thr 315 shifts to allow binding of Imatinib. It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.[2] Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal Tumors. In BCR-Abl, Imatinib is bound by residues ____, firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase. [3]

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
  3. ↑ 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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