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