Imatinib
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| Systematic (IUPAC) name | |
| 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide | |
| Clinical data | |
| Trade names | Gleevec |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a606018 |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | D(AU) D(US) |
| Legal status | POM (UK) ℞-only (US) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 98% |
| Protein binding | 95% |
| Metabolism | Hepatic (mainly CYP3A4-mediated) |
| Half-life | 18 hours (imatinib) 40 hours (active metabolite) |
| Excretion | Fecal (68%) and renal (13%) |
| Identifiers | |
| CAS number | 152459-95-5  220127-57-1 (mesilate) |
| ATC code | L01XE01 |
| PubChem | CID 5291 |
| DrugBank | APRD01028 |
| ChemSpider | 5101 |
| UNII | BKJ8M8G5HI |
| KEGG | D08066 |
| ChEBI | CHEBI:45783 |
| ChEMBL | CHEMBL941 |
| Chemical data | |
| Formula | C29H31N7O |
| Mol. mass | 493.603 g/mol 589.7 g/mol (mesilate) |
| SMILES | eMolecules & PubChem |
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Imatinib (originally STI571) is a drug used to treat certain cancers. It is marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia/Latin America) as its mesylate salt, imatinib mesilate (INN).
Imatinib is the first of a new class of drugs that act by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than non-specifically inhibiting and killing all rapidly dividing cells. Imatinib was a model for other targeted therapies that inhibited the class of enzymes, tyrosine kinases.
It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and some other diseases. By 2011, Gleevec has been FDA approved to treat ten different cancers.
In CML, the tyrosine kinase enzyme ABL in white blood cells is locked in its activated form. This causes the excessive proliferation and high white blood cell count which is characteristic of CML. Imatinib binds to the site of tyrosine kinase activity, and prevents its activity, causing tumor cell death (apoptosis).
In January 2012, three of the developers of imatinib were awarded the Japan Prize for their work.[1][2]
Contents |
[edit] History
Imatinib was developed in the late 1990s by biochemist Nicholas Lydon, a former researcher for Novartis, and oncologist Brian Druker of Oregon Health and Science University (OHSU). Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini, a physician scientist and hematologist at University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital in London, UK, and later on by Charles Sawyers of Memorial Sloan-Kettering Cancer Center,[3] who led the clinical trials confirming its efficacy in CML.[4]
Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.[5]
Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the "magic bullet" to cure cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for "converting a fatal cancer into a manageable chronic condition".[3]
Gleevec also holds the record for the drug with the fastest approval time by the FDA. According to Brian Druker, one of the developers of Imatinib, the biggest obstacle to being approved was the name of the drug. At that time, the drug was being called "Glivec", which is also the current spelling in most parts of the world. However, the United States Food and Drug Administration did not want people to mispronounce "Glivec" as "GLIE-VEC" which could be confused with a diabetic drug at the time. Therefore, Novartis, the pharmaceutical company who markets Gleevec, changed the name of "Glivec" to include two "e's" and avoid the phonetic confusion: Gleevec. Shortly thereafter, Gleevec was approved by the FDA.
[edit] Uses
[edit] Clinical
Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit.[6] Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis.
[edit] Chronic myelogenous leukemia
The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome (Ph)-positive CML, both in adults and children. The drug is approved in multiple Ph-positive cases CML, including after stem cell transplant, in blast crisis, and newly diagnosed.[7]
[edit] Gastrointestinal stromal tumors
The FDA first granted approval for advanced GIST patients in 2002. On February 1st, 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.[8] The drug is also approved in unresectable KIT-positive GISTs.[7]
[edit] Other approvals
The FDA has approved imatinib for use in adult patients with relapsed or refractory Ph-positive ALL, myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, aggressive systemic mastocytosis (ASM) without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.[7]
[edit] Plexiform neurofibromas
For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-kit tyrosine kinase blocking properties of imatinib.[9][10][11][12][13]
[edit] Experimental
Imatinib may also have a role in the treatment of pulmonary hypertension. It has been shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.[14] In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis in mice without[15] or with diabetes.[16]
Mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[17]
In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP), which selectively increases the production and accumulation of neurotoxic beta-amyloid plaques. This suggests molecules that target at GSAP and are able to cross blood-brain barrier are potential therapeutic agents for treating Alzheimer's disease.[18] Another study suggests that imatinib may not need to cross the blood-brain barrier to be effective at treating Alzheimer's, as the research indicates the production of beta-amyloid may begin in the liver. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain.[19] It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms.[20]
[edit] Adverse effects
The most common side effects include weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), headache, edema, nausea, rash, and musculoskeletal pain.[21]
Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.[22]
If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.[23]
[edit] Pharmacology
[edit] Pharmacokinetics
Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively. It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.[24]
[edit] Mechanism of action
Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.
There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.[25] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[26]
Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.[27] Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.[28]
[edit] Interactions
Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St. John's Wort reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.[21]
As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.[29]
[edit] Costs
The cost of Gleevec for CML is $32,000[30][31] to $98,000[32] a year, and for GIST is $64,800 a year.[33]
Prices for a 100 mg pill of Gleevec internationally range from $20 to $30,[34] although generic imatinib is cheaper.[35]
[edit] Legal challenge to generics
In 2007, imatinib became a test case through which Novartis challenged India's patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Doctors without Borders argues a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines.[36] On 6 August 2007, the Madras High Court dismissed the writ petition filed by Novartis challenging the constitutionality of Section 3(d) of Indian Patent Act, and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question. As of 2008[update] the case is unresolved[citation needed].
[edit] See also
[edit] References
- ^ Rowley to receive Japan Prize for her role in the development of targeted cancer therapy Eurekalert, Press release, 24-Jan-2012
- ^ Leukemia Drug and Magnet Material Net Japan Prizes by Dennis Normile, Science Insider, 25 January 2012
- ^ a b A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, November 2, 2009
- ^ Gambacorti-Passerini C (2008). "Part I: Milestones in personalised medicine--imatinib". Lancet Oncology 9 (600): 600. doi:10.1016/S1470-2045(08)70152-9. PMID 18510992.
- ^ Druker BJ, Lydon NB (January 2000). "Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia". J. Clin. Invest. 105 (1): 3–7. doi:10.1172/JCI9083. PMC 382593. PMID 10619854. http://www.jci.org/cgi/content/full/105/1/3.
- ^ Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL (July 2006). "Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial". Cancer 107 (2): 345–51. doi:10.1002/cncr.21996. PMID 16779792.
- ^ a b c "FDA Highlights and Prescribing Information for Gleevec(imatinib mesylate)". http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf.
- ^ "Prolonged Use of Imatinib in GIST Patients Leads to New FDA Approval". http://www.onclive.com/web-exclusives/Prolonged-Use-of-Imatinib-in-GIST-Patients-Leads-to-New-FDA-Approval.
- ^ Yang, FC; Ingram, DA; Chen, S; Zhu, Y; Yuan, J; Li, X; Yang, X; Knowles, S et al (2008). "Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow.". Cell 135 (3): 437–48. doi:10.1016/j.cell.2008.08.041. PMC 2788814. PMID 18984156. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2788814.
- ^ "Gleevec Holds Potential As First Drug To Successfully Treat Neurofibromatosis, Scientists Report", Science Daily, October 31, 2008
- ^ "Gleevec NF1 Trial"
- ^ "GIST in Neurofibromatosis 1"
- ^ "Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas (0908-09)" (Suspended)
- ^ Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M (June 2009). "Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition". Transplant. Proc. 41 (5): 1969–71. doi:10.1016/j.transproceed.2009.02.100. PMID 19545770.
- ^ Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J (April 2003). "LRP: role in vascular wall integrity and protection from atherosclerosis". Science 300 (5617): 329–32. doi:10.1126/science.1082095. PMID 12690199.
- ^ Lassila M, Allen TJ, Cao Z, et al. (May 2004). "Imatinib attenuates diabetes-associated atherosclerosis". Arterioscler. Thromb. Vasc. Biol. 24 (5): 935–42. doi:10.1161/01.ATV.0000124105.39900.db. PMID 14988091.
- ^ Reeves PM, Bommarius B, Lebeis S, et al. (July 2005). "Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases". Nat. Med. 11 (7): 731–9. doi:10.1038/nm1265. PMID 15980865.
- ^ He G, Luo W, Li P, et al. (September 2010). "Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease". Nature 467 (7311): 95–8. doi:10.1038/nature09325. PMC 2936959. PMID 20811458. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2936959.
- ^ http://www.msnbc.msn.com/id/41971124/ns/health-alzheimers_disease/
- ^ Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JAR (July 2008). "Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial" (Subscription required). The Lancet 372 (9634): 216–233. doi:10.1016/S0140-6736(08)61075-2. PMID 18640458.
- ^ a b Haberfeld, H, ed. (2009) (in German). Austria-Codex (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
- ^ Kerkelä R, Grazette L, Yacobi R, et al. (August 2006). "Cardiotoxicity of the cancer therapeutic agent imatinib mesylate". Nat. Med. 12 (8): 908–16. doi:10.1038/nm1446. PMID 16862153.
- ^ Shima H, Tokuyama M, Tanizawa A et al (2011). "Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia". J. Pediatr (Online). doi:10.1016/j.jpeds.2011.03.046. PMID 21592517.
- ^ Scheinfeld N, Schienfeld N (February 2006). "A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases". J Drugs Dermatol 5 (2): 117–22. PMID 16485879.
- ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
- ^ Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L (February 2003). "Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias". Lancet Oncol. 4 (2): 75–85. doi:10.1016/S1470-2045(03)00979-3. PMID 12573349.
- ^ Deininger MW, Druker BJ (September 2003). "Specific targeted therapy of chronic myelogenous leukemia with imatinib". Pharmacol. Rev. 55 (3): 401–23. doi:10.1124/pr.55.3.4. PMID 12869662.
- ^ Vigneri P, Wang JY (February 2001). "Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase". Nat. Med. 7 (2): 228–34. doi:10.1038/84683. PMID 11175855.
- ^ Klopp, T, ed. (2010) (in German). Arzneimittel-Interaktionen (2010/2011 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-207-1.
- ^ Schiffer CA (July 2007). "BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia". N. Engl. J. Med. 357 (3): 258–65. doi:10.1056/NEJMct071828. PMID 17634461.
- ^ As Pills Treat Cancer, Insurance Lags Behind, By ANDREW POLLACK, New York Times, April 14, 2009
- ^ Living With a Formerly fatal Blood Cancer, By JANE E. BRODY, New York Times, January 18, 2010
- ^ Kelley RK, Venook AP (August 2010). "Nonadherence to imatinib during an economic downturn". N. Engl. J. Med. 363 (6): 596–8. doi:10.1056/NEJMc1004656. PMID 20818898.
- ^ Patented Medicine Review Board (Canada). Report on New Patented Drugs - Gleevec.
- ^ pharmacychecker.com
- ^ Médecins Sans Frontières. "As Novartis Challenges India's Patent Law, MSF Warns Access to Medicines Is Under Threat", 2006-09-26. Accessed 2006-02-10.
[edit] External links
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