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  • Picture: http://www.pediatricgist.org/PediatricGIST/Treatment/Gleevec/tabid/69/Default.aspx
  • 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: 164-17
  • 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: 1962-1964Druker 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.
  • First picture - 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.
  • 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
  • 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: 6http://imaging.ubmmedica.com/cancernetwork/journals/oncology/200705/ONC05152007p00654f1.jpg
  • Brunton LL, Chabner BA, Knollman BC, eds. Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011.
  • Picture: 400 SLSL.Drugs.com. http://www.drugs.com/imprints/400-sl-sl-12647.html
  • Context: 1)Product Information: GLEEVEC(R) oral tablet , imatinibmesylate oral tablet . Novartis Pharmaceutical Corporation, East Hanover, NJ, 2005. 2)Truven Health Products. N.p., n.d. Web. 12 Nov. 2012. <http://www.thomsonhc.com/micromedex2/librarian/ND_T/evidencexpert>.Picture: "Pathway: Imatinib Pathway, Pharmacokinetics/Pharmacodynamics   [UNDER REVIEW]." Imatinib Pathway, Pharmacokinetics/Pharmacodynamics [PharmGKB]. N.p., n.d. Web. 11 Nov. 2012. <http://www.pharmgkb.org/pathway/PA164713427>.
  • Picture: "Pathway: Imatinib Pathway, Pharmacokinetics/Pharmacodynamics   [UNDER REVIEW]." Imatinib Pathway, Pharmacokinetics/Pharmacodynamics [PharmGKB]. N.p., n.d. Web. 11 Nov. 2012.
  • Picture: de Kogel C E , Schellens J H M The Oncologist 2007;12:1390-1394Context: 1) Product Information: GLEEVEC(R) oral tablet , imatinibmesylate oral tablet . Novartis Pharmaceutical Corporation, East Hanover, NJ, 2005.2)"The Oncologist." Imatinib. N.p., n.d. Web. 11 Nov. 2012. <http://theoncologist.alphamedpress.org/content/12/12/1390.full>.
  • Context: 1)Truven Health Products. N.p., n.d. Web. 12 Nov. 2012. <http://www.thomsonhc.com/micromedex2/librarian/ND_T/evidencexpert>.Picture: "ScienceDirect.com" ScienceDirect.com. N.p., n.d. Web. 12 Nov. 2012. <http://www.sciencedirect.com/science/article/pii/S0039914011006862>.
  • Picture: DMPK and Degradation Metabolites Using Microbial Biotransformation. N.p., n.d. Web. 11 Nov. 2012. <http://www.hyphadiscovery.co.uk/production_of_mammalian_agrochemical_microbial_metabolites.html>
  • Source:ImatinibMesylate. Micromedex 2.0. http://www.thomsonhc.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch
  • Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. PubMed.gov. 2005;44(9):879-94. http://www.ncbi.nlm.nih.gov/pubmed/16122278. Accessed November 11, 2012.Kogel CE, Schellens JHM, Imatinib. The Oncologist. 2007. http://theoncologist.alphamedpress.org/content/12/12/1390.full Accessed November 18, 2012.Gschwind, HP. Metabolism and disposition of imatinibmesylate in healthy volunteers. Drug Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124 http://dmd.aspetjournals.org/content/33/10/1503.full. Accessed November 10, 2012. Picture: Van Veen, H. Human Breast Cancer Resistance Protein. University of Cambridge http://www.phar.cam.ac.uk/research/vanveen/vanveenresearch.html.
  • Gschwind, HP. Metabolism and disposition of imatinibmesylate in healthy volunteers. Drug Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124 http://dmd.aspetjournals.org/content/33/10/1503.full. Accessed November 10, 2012.

Transcript

  • 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 1990s 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. Distribution51. 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. Imatiniblocation ofmetabolism. 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-oxidizeddemethylatedpiperazine 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. References1. Faderl S, Talpaz M, Estrov Z, OBrian S, Kurzrock R, KantarjianH. The Biology of Chronic Myeloid Leukemia. New England Journal of Medicine. 1999; 341: 164-1722. DeVita V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenbergs Cancer: Principles and Practice of Oncology. 9th ed. North American edition: Lippincott Williams & Wilkins; 2011: 1962-19643. 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. AbosluteBioavailavbility of Imatinib(Gleevec®) Orally versus Intravenous Infusion. Clinical Journal of Pharmacology. 2004; 44: 158-1627. 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