Imatinib (Gleevec) is a tyrosine kinase inhibitor developed to treat chronic myelogenous leukemia (CML). [1] It works by binding to the Bcr-Abl protein created by a chromosomal translocation, blocking its ability to phosphorylate proteins and activate cancer-causing pathways. [2-4] Imatinib is well-absorbed orally and highly protein bound. It undergoes hepatic metabolism primarily via CYP3A4 and is eliminated mostly in the feces. The main metabolite is an active N-demethylated derivative. Dose adjustments are generally not needed due to its variable clearance. [5-11]

1. Imatinib
Gleevec®
Scott Denno, Michael Retz, Daniel Lasselle, Matt Wright, Emily Russell
http://www.pediatricgist.org/PediatricGIST/Treatment/Gleevec/tabid/6
9/Default.aspx

2. 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.

3. 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

4. (Figure 2. shows the binding of Bcr/Abl to ATP and then to Gleevec®.)
http://www.pitt.edu/~super1/lecture/lec45951/004.htm

5. 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

6. (Figure 3. shows the transduction pathways implicated with Bcr/Abl activation.)
http://imaging.ubmmedica.com/cancernetwork/journals/oncology/2007
05/ONC05152007p00654f1.jpg

7. Distribution5
1. Protein Binding = 95%
2. VD = 6.2 ± 2.2 L/Kg or 434 L for a 70 Kg
Patient

8. Protein Binding5
 Primarily with Albumin and α1 – acid
Glycoprotein
 Albumin binds with weak acids
 α1 – acid Glycoprotein binds with
weak bases

9. Volume of Distribution5
 Vd(Imatinib) > 40 L
 Protein binding usually lowers Vd

10. 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

11. 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

12. 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

13. Metabolism
 Hepatic metabolism7,8
 Mainly via CYP3A4 enzyme7
 Other CYP-450 isozymes play minor role
 CYP1A2, CYP2D6, CYP2C9, and CYP2C197

14. 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.

15. Metabolism
 N-desmethyl-imatinib
(“CGP74588”)
 N-
demethylatedpiperazine
derivative7
 Main circulating
metabolite in humans7
 MW = 479.587
 Imatinib and N-
desmethyl-imatinib are
Chemical structure of the N- both mainly N-oxidized
demethylatedpiperazine derivate. in the liver8
de Kogel C E , Schellens J H M The Oncologist 2007;12:1390-1394

16. N-desmethyl-imatinib (“CGP74588”)
 Active
 Shows 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.
"ScienceDirect.com" ScienceDirect.com. N.p., n.d. Web. 12 Nov. 2012.

17. Other possible metabolites
http://www.hyphadiscovery.co.uk/production_of_mammalian_agrochemi
cal_microbial_metabolites.html

18. Excretion9
 Urinary to Fecal Ratio is 1:5
 Renal Excretion = 13% of dose
 5% unchanged in urine
 Fecal Excretion = 70% of the dose
 20% unchanged in feces
 Elimination Half-life about 18 hrs
 Excretion generally the same in adults and
children

19. Excretion
 Eliminated 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 days
 80% dose recovered in 7 days
http://www.phar.cam.ac.uk/research/vanveen/vanveenresearch.html

20. Excretion9
 Though clearance
is variable based
on patient weight
and age, the
manufacturer does
not recommend
dose adjustment
 Monitoring is
important to avoid
Figure 6. Imatinib plasma
toxicity concentration shown as
concentration(nmol/L) v. time(h).
http://dmd.aspetjournals.org/content/33/10/1503.full

21. References
1. Faderl S, Talpaz M, Estrov Z, O'Brian S, Kurzrock R, KantarjianH. 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: 6
5. 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. AbosluteBioavailavbility of Imatinib(Gleevec®) Orally versus
Intravenous Infusion. Clinical Journal of Pharmacology. 2004; 44: 158-162
7. Product Information: GLEEVEC(R) oral tablet , imatinibmesylate 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 imatinibmesylate in healthy volunteers. Drug
Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124