Gleevec group presentation#1
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Transcript of Gleevec group presentation#1
http://www.pediatricgist.org/PediatricGIST/Treatment/Gleevec/tabid/69/Default.aspx
Imatinib Gleevec®
Scott Denno, Michael Retz, Daniel Lasselle, Matt Wright, Emily Russell
Gleevec® (Imatinib)
A tyrosine Kinase Inhibitor developed in the late 1990's to treat Chronic Mylogenous Leukemia which is a cancer of the lymphatic system and bone. 1
CML is caused by a translocation of the 9th and 22nd chromosomes.1
Causes the Bcr-Abl oncogene to be created.1
Responsible for the activation of many signal transduction pathways that cause the characteristics of CML.
Mechanism of Action
Imatinib binds to Bcr/Abl protein very close to the binding site of ATP, blocking ATP from binding.2
Without the binding of ATP, Bcr/Abl cannot phosphorylate substrate proteins.2
Imatinib is very specific to this sub-family of receptor tyrosine kinases.2
http://www.pitt.edu/~super1/lecture/lec45951/004.htm
(Figure 2. shows the binding of Bcr/Abl to ATP and then to Gleevec®.)
Mechanism of Action
Blocking the ability of Bcr/Abl stops several transduction pathways that cause the excessive proliferation of partially differentiated cells that lead to CML.4
The main oncogenes that are inhibited are Ras, Myc, and STAT.4
Each of these oncogenes cause a signal cascade that cause cell proliferation.4
http://imaging.ubmmedica.com/cancernetwork/journals/oncology/200705/ONC05152007p00654f1.jpg
(Figure 3. shows the transduction pathways implicated with Bcr/Abl activation.)
Distribution5
1. Protein Binding = 95%
2. VD = 6.2 ± 2.2 L/Kg or 434 L for a 70 Kg Patient
Protein Binding5
Primarily with Albumin and α1 – acid GlycoproteinAlbumin binds with weak acidsα1 – acid Glycoprotein binds with
weak bases
Volume of Distribution5
Vd (Imatinib) > 40 L
Protein binding usually lowers Vd
Absorption6
All doses of Imatinib should be taken with a meal and a large glass of water
Doses of 400 mg or 600 mg should be administered once daily
Doses of 800 mg should be administered as 400 mg twice a day
Can be dissolved in water or apple juice for patients having difficulty swallowing
Absorption6
Imatinib is well absorbed after oral administration
Maximal drug concentration (Cmax) achieved within 2 to 4 hours post dose.
Mean absolute bioavailability is 98%
Mean imatinib AUC increases proportionally with increasing doses ranging from 25 to 1,000 mg
Absorption6
There is no significant change in the pharmacokinetics of Imatinib upon repeated dosing
Accumulation is 1.5-2.5-fold at steady state when Imatinib is dosed once daily
At clinically relevant concentrations Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly albumin and alpha-1 acid glycoprotein
Metabolism
Hepatic metabolism7,8
Mainly via CYP3A4 enzyme7
Other CYP-450 isozymes play minor roleCYP1A2, CYP2D6, CYP2C9, and
CYP2C197
Figure 4. Imatinib location of metabolism.
Picture: "Pathway: Imatinib Pathway, Pharmacokinetics/Pharmacodynamics  [UNDER REVIEW]."
Imatinib Pathway, Pharmacokinetics/Pharmacodynamics [PharmGKB]. N.p., n.d. Web. 11 Nov. 2012.
de Kogel C E , Schellens J H M The Oncologist 2007;12:1390-1394
Metabolism
N-desmethyl-imatinib (“CGP74588”)N-demethylated
piperazine derivative7
Main circulating metabolite in humans7
MW = 479.587
Imatinib and N-desmethyl-imatinib are both mainly N-oxidized in the liver8
Chemical structure of the N-demethylated piperazine derivate.
"ScienceDirect.com" ScienceDirect.com. N.p., n.d. Web. 12 Nov. 2012.
N-desmethyl-imatinib (“CGP74588”)ActiveShows in vitro potency similar to parent drug7
Plasma AUC of metabolite ~15% that of parent drug7
Figure 5. Shows relative plasma AUC of Imatinib and GCP.
http://www.hyphadiscovery.co.uk/production_of_mammalian_agrochemical_microbial_metabolites.html
Other possible metabolites
Excretion9
Urinary to Fecal Ratio is 1:5
Renal Excretion = 13% of dose5% unchanged in urine
Fecal Excretion = 70% of the dose20% unchanged in feces
Elimination Half-life about 18 hrs
Excretion generally the same in adults and children
http://www.phar.cam.ac.uk/research/vanveen/vanveenresearch.html
ExcretionEliminated mainly as metabolites
(25% remained unchanged)9
Actively secreted in bile by several drug transports from the ATP binding cassette superfamily, mainly ABCB1(P-glycoprotein) and ABCG2 (Bcrp)10
4 healthy volunteers11
25% dose recovered in 2 days80% dose recovered in 7 days
Excretion9
Though clearance is variable based on patient weight and age, the manufacturer does not recommend dose adjustment
Monitoring is important to avoid toxicity
Figure 6. Imatinib plasma concentration shown as concentration(nmol/L) v. time(h).
http://dmd.aspetjournals.org/content/33/10/1503.full
References
1. Faderl S, Talpaz M, Estrov Z, O'Brian S, Kurzrock R, Kantarjian H. The Biology of Chronic Myeloid Leukemia. New England Journal of Medicine. 1999; 341: 164-172
2. DeVita V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 9th ed. North American edition: Lippincott Williams & Wilkins; 2011: 1962-1964
3. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
4. Jabbour E, Cortes J, Kantarjian H. Optimal First-Line Treatment of Chronic Myeloid Leukemia: How to Use Imatinib and What Role for Newer Drugs. Oncology.
2007; 21: 65. Brunton LL, Chabner BA, Knollman BC, eds. Pharmacological Basis of Therapeutics.
12th ed. New York, NY: McGraw-Hill; 2011.6. Peng B, Dutreix C, et al. Aboslute Bioavailavbility of Imatinib (Gleevec®) Orally versus
Intravenous Infusion. Clinical Journal of Pharmacology. 2004; 44: 158-1627. Product Information: GLEEVEC(R) oral tablet , imatinib mesylate oral tablet . Novartis Pharmaceutical
Corporation, East Hanover, NJ, 2005.8. Truven Health Products. N.p., n.d. Web. 12 Nov. 2012. 9. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. PubMed.gov.
2005;44(9):879-94. 10. Kogel CE, Schellens JHM, Imatinib. The Oncologist. 2007. 11. Gschwind, HP. Metabolism and disposition of imatinib mesylate in healthy volunteers.
Drug Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124