Imatinib

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=March 2024}}

{{infobox drug | verifiedrevid = 459451238 | image = Imatinib2DACS.svg | image_class = skin-invert-image | width = 250 | alt = | image2 = File:Imatinib structure.png | image_class2 = bg-transparent | width2 = 280 | alt2 = Ball-and-stick model of the imatinib molecule | caption =  | pronounce = ih-MAT-ih-nib | tradename = Gleevec, Glivec, others | Drugs.com = {{drugs.com|monograph|imatinib-mesylate}} | MedlinePlus = a606018 | DailyMedID = Imatinib | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title = Imatinib (Gleevec) Use During Pregnancy | date = 27 August 2018 | publisher = Drugs.com | url = https://www.drugs.com/pregnancy/imatinib.html | access-date = 16 February 2020 | archive-date = 17 February 2020 | archive-url = https://web.archive.org/web/20200217055034/https://www.drugs.com/pregnancy/imatinib.html | url-status = live }}</ref> | pregnancy_category = | routes_of_administration = By mouth | class = Tyrosine kinase inhibitor<ref name="AHFS2017">{{cite web | title = Imatinib Mesylate | url = https://www.drugs.com/monograph/imatinib-mesylate.html | publisher = The American Society of Health-System Pharmacists | access-date = 8 January 2017 | url-status = live | archive-url = https://web.archive.org/web/20170116192526/https://www.drugs.com/monograph/imatinib-mesylate.html | archive-date = 16 January 2017 }}</ref> | ATC_prefix = L01 | ATC_suffix = EA01 | ATC_supplemental =  | legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title = Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | date = 21 June 2022 | website = Therapeutic Goods Administration (TGA) | url = https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date = 30 March 2024 | archive-date = 6 July 2023 | archive-url = https://web.archive.org/web/20230706023149/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | url-status = live }}</ref> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Gleevec FDA label">{{cite web | title = Gleevec- imatinib mesylate tablet | date = 1 March 2024 | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=211ef2da-2868-4a77-8055-1cb2cd78e24b | access-date = 2 July 2024 }}</ref><ref name="Imkeldi FDA label">{{cite web | title = Imkeldi- imatinib oral solution | date = 5 December 2024 | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=26658bb7-9ba1-a10e-e063-6394a90a172e | access-date = 23 December 2024 }}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Glivec EPAR">{{cite web | title = Glivec EPAR | date = 7 November 2001 | website = European Medicines Agency | url = https://www.ema.europa.eu/en/medicines/human/EPAR/glivec | access-date = 2 July 2024 }}</ref> | legal_UN =  | legal_UN_comment = | legal_status =

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 152459-95-5 | CAS_supplemental = <br />{{CAS|220127-57-1}}(mesilate) | PubChem = 5291 | IUPHAR_ligand = 5687 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00619 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5101 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = BKJ8M8G5HI | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08066 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 45783 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 941 | NIAID_ChemDB = | PDB_ligand = STI | synonyms = STI-571

| IUPAC_name = 4-[(4-methylpiperazin-1-yl)methyl]-''N''-(4-methyl-3-<nowiki/>{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide | C = 29 | H = 31 | N = 7 | O = 1 | SMILES = Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)NC(=O)c4ccc(cc4)CN5CCN(CC5)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34) | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = KTUFNOKKBVMGRW-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Imatinib''', sold under the brand names '''Gleevec''' and '''Glivec''' (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer.<ref name="AHFS2017" /> Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β.<ref>{{cite journal | vauthors = Green KN, Crapser JD, Hohsfield LA | title = To Kill a Microglia: A Case for CSF1R Inhibitors | journal = Trends in Immunology | volume = 41 | issue = 9 | pages = 771–784 | date = September 2020 | pmid = 32792173 | pmc = 7484341 | doi = 10.1016/j.it.2020.07.001 }}</ref><ref>{{cite journal | vauthors = Mun SH, Park PS, Park-Min KH | title = The M-CSF receptor in osteoclasts and beyond | journal = Experimental & Molecular Medicine | volume = 52 | issue = 8 | pages = 1239–1254 | date = August 2020 | pmid = 32801364 | pmc = 8080670 | doi = 10.1038/s12276-020-0484-z }}</ref> Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph<sup>+</sup>), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.<ref name="AHFS2017" />

Common side effects include vomiting, diarrhea, muscle pain, headache, and rash. Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure. Use during pregnancy may result in harm to the baby. Imatinib works by stopping the Bcr-Abl tyrosine-kinase. This can slow growth or result in programmed cell death of certain types of cancer cells.<ref name="AHFS2017" />

Imatinib was approved for medical use in the United States in 2001.<ref name="AHFS2017" /> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | location = Geneva | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access = free }}</ref> A generic version became available in the UK as of 2017.<ref>{{cite web | title = Oxford Pharmacy Store Generic Imatinib | url = http://oxfordpharmacystore.co.uk/latest_news/generic-imatinib/ | website = oxfordpharmacystore.co.uk | access-date = 1 April 2017 | url-status = live | archive-url = https://web.archive.org/web/20170402081046/http://oxfordpharmacystore.co.uk/latest_news/generic-imatinib/ | archive-date = 2 April 2017 }}</ref>

==Medical uses== Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. In 2006 the FDA expanded approved use to include dermatofibrosarcoma protuberans (DFSP), myelodysplastic/myeloproliferative diseases (MDS/MPD), and aggressive systemic mastocytosis (ASM).<ref name="citec85d6cf8">{{Cite journal | title = Gleevec Gains Simultaneous FDA Approval for Five Rare, Life-Threatening Disorders | volume = 15 | issue = 11 | date = 1 November 2006 | url = https://www.cancernetwork.com/gastrointestinal-cancer/gleevec-gains-simultaneous-fda-approval-five-rare-life-threatening-disorders | access-date = 10 June 2020 | website = Cancer Network | series = Oncology NEWS International Vol 15 No 11 | language = en | archive-date = 10 June 2020 | archive-url = https://web.archive.org/web/20200610130239/https://www.cancernetwork.com/gastrointestinal-cancer/gleevec-gains-simultaneous-fda-approval-five-rare-life-threatening-disorders | url-status = dead }}</ref>

Imatinib is considered to be a very effective treatment for CML, and has been shown to improve outcomes for people with this type of leukemia. It can also be used to treat some types of ALL, but is not considered a standard of care for ALL. In many cases, imatinib can induce a complete cytogenetic response (CCyR) and major molecular response (MMR) and many patients can have a long-term remission. It is also used to maintain remission in chronic phase CML patients.

While imatinib is a very effective treatment for CML and some types of ALL, it is not a cure for leukemia. Instead, it is a 'chronic therapy' that helps to control the disease and prevent it from progressing. Some patients may need to continue taking imatinib for an extended period of time to maintain remission, and some patients may eventually require additional treatment options.

===Chronic myelogenous leukemia=== The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple contexts of Philadelphia chromosome-positive CML, including after stem cell transplant, in blast crisis, newly diagnosed, and accelerated phase.<ref name="FDA">{{cite web | title = FDA Highlights and Prescribing Information for Gleevec(imatinib mesylate) | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf | url-status = live | archive-url = https://web.archive.org/web/20140913120652/http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf | archive-date = 13 September 2014 }}</ref><ref>{{cite book | vauthors = Flynn JP, Gerriets V | chapter = Imatinib | title = StatPearls | date = 2025 | pmid = 31869140 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK551676/ | access-date = 2025-11-16 | place = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref>

Due in part to the development of imatinib and related drugs, the five-year survival rate for people with chronic myeloid leukemia increased from 31% in 1993, to 59% in 2009,<ref>{{cite web | title = Leukemia – Chronic Myeloid – CML: Statistics | Cancer.Net | date = 26 June 2012 | url = http://www.cancer.net/cancer-types/leukemia-chronic-myeloid-cml/statistics | url-status = live | archive-url = https://web.archive.org/web/20141112155938/http://www.cancer.net/cancer-types/leukemia-chronic-myeloid-cml/statistics | archive-date = 12 November 2014 }}</ref> to 70% in 2016.<ref>{{cite web | title = Cancer Stat Facts: Leukemia – Chronic Myeloid Leukemia (CML) | url = https://seer.cancer.gov/statfacts/html/cmyl.html | website = Cancer.gov | access-date = 17 April 2020 | archive-date = 1 February 2020 | archive-url = https://web.archive.org/web/20200201203304/https://seer.cancer.gov/statfacts/html/cmyl.html | url-status = live }}</ref> By 2023, the five year survival rate for people with chronic myeloid leukemia had risen to 90%.<ref>{{cite web | title = Survival statistics for chronic myeloid leukemia | date = September 2022 | url = https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/prognosis-and-survival/survival-statistics#:~:text=The%205%2Dyear%20relative%20survival,sex%20in%20the%20general%20population | access-date = 13 December 2023 | archive-date = 13 December 2023 | archive-url = https://web.archive.org/web/20231213065443/https://cancer.ca/en/cancer-information/cancer-types/chronic-myeloid-leukemia-cml/prognosis-and-survival/survival-statistics#:~:text=The%205%2Dyear%20relative%20survival,sex%20in%20the%20general%20population | url-status = live }}</ref> Starting from 2011, it became clear that CML patients who continue to respond to imatinib have the same or almost the same life expectancy as the general population.<ref>{{cite journal | vauthors = Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D'Emilio A, Stagno F, le Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Piazza R, Valsecchi MG, Kim DW | title = Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib | journal = Journal of the National Cancer Institute | volume = 103 | issue = 7 | pages = 553–561 | date = April 2011 | pmid = 21422402 | doi = 10.1093/jnci/djr060 | doi-access = free }}</ref>

===Gastrointestinal stromal tumors=== The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.<ref name="onclive">{{cite web | title = Prolonged Use of Imatinib in GIST Patients Leads to New FDA Approval | work = OncLive | date = February 2012 | url = http://www.onclive.com/web-exclusives/Prolonged-Use-of-Imatinib-in-GIST-Patients-Leads-to-New-FDA-Approval | url-status = live | archive-url = https://web.archive.org/web/20120204082247/http://www.onclive.com/web-exclusives/Prolonged-Use-of-Imatinib-in-GIST-Patients-Leads-to-New-FDA-Approval | archive-date = 4 February 2012 }}</ref> The drug is also approved in unresectable KIT-positive GISTs.<ref name="FDA" />

===Dermatofibrosarcoma protuberans (DFSP)=== The FDA granted approval for the treatment of dermatofibrosarcoma protuberans (DFSP) patients in 2006.<ref name="citec85d6cf8" /> Specifically adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). Prior to approval DFSP was considered unresponsive to chemotherapy treatments.

===Other=== The FDA has approved imatinib for use in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia 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.<ref name="FDA" /> On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.<ref>{{cite web | title = FDA approves Gleevec for children with acute lymphoblastic leukemia | date = 25 January 2013 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336868.htm | work = FDA News Release | publisher = US Food and Drug Administration | access-date = 3 April 2013 | url-status = dead | archive-url = https://web.archive.org/web/20130310094645/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336868.htm | archive-date = 10 March 2013 }}</ref>

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.<ref name="Yang_2008">{{cite journal | vauthors = Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW | title = Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow | journal = Cell | volume = 135 | issue = 3 | pages = 437–448 | date = October 2008 | pmid = 18984156 | pmc = 2788814 | doi = 10.1016/j.cell.2008.08.041 | doi-access = free }} *{{lay source |template = cite press release|url=https://www.sciencedaily.com/releases/2008/10/081030123837.htm|title = Gleevec Holds Potential As First Drug To Successfully Treat Neurofibromatosis, Scientists Report|date = 31 October 2008 |website = ScienceDaily }}</ref><ref>{{cite web | title = Gleevec NF1 Trial | url = http://www.nfcure.org/newnf1trial/gleevecnf1trial.html | publisher = Nfcure.org | access-date = 3 April 2013 | url-status = dead | archive-url = https://web.archive.org/web/20120420015449/http://nfcure.org/newnf1trial/gleevecnf1trial.html | archive-date = 20 April 2012 }}</ref><ref>{{cite web | title = GIST in Neurofibromatosis 1 | date = 14 May 2010 | url = http://www.gistsupport.org/about-gist/gist-in-neurofibromatosis-1.php | publisher = Gistsupport.org | access-date = 3 April 2013 | url-status = dead | archive-url = https://web.archive.org/web/20130329203014/http://www.gistsupport.org/about-gist/gist-in-neurofibromatosis-1.php | archive-date = 29 March 2013 }}</ref><ref>{{cite web | title = "Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas (0908-09)" (Suspended) | url = http://clinicaltrials.gov/ct2/show/NCT01140360 | publisher = Clinicaltrials.gov | access-date = 3 April 2013 | url-status = live | archive-url = https://web.archive.org/web/20130703202412/http://www.clinicaltrials.gov/ct2/show/NCT01140360 | archive-date = 3 July 2013 }}</ref> There have been several phase 2 trials of imatinib for aggressive fibromatosis.<ref>{{cite journal | vauthors = Kasper B, Gruenwald V, Reichardt P, Bauer S, Rauch G, Limprecht R, Sommer M, Dimitrakopoulou-Strauss A, Pilz L, Haller F, Hohenberger P | title = Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG) | journal = European Journal of Cancer | volume = 76 | pages = 60–67 | date = May 2017 | pmid = 28282612 | doi = 10.1016/j.ejca.2017.02.001 | s2cid = 3630670 }}</ref><ref>{{cite journal | vauthors = Mangla A, Agarwal N, Schwartz G | title = Desmoid Tumors: Current Perspective and Treatment | journal = Current Treatment Options in Oncology | volume = 25 | issue = 2 | pages = 161–175 | date = February 2024 | pmid = 38270798 | pmc = 10873447 | doi = 10.1007/s11864-024-01177-5 | doi-access = free }}</ref>

==Contraindications and cautions== The only known contraindication to imatinib is hypersensitivity to imatinib.<ref name="EMC">{{cite web | title = Glivec Tablets – Summary of Product Characteristics (SPC) | work = electronic Medicines Compendium | publisher = Novartis Pharmaceuticals UK Ltd | url = http://www.medicines.org.uk/emc/medicine/15014/SPC/GLIVEC+Tablets/ | url-status = live | archive-url = https://web.archive.org/web/20140201204756/http://www.medicines.org.uk/emc/medicine/15014/SPC/GLIVEC+Tablets/ | archive-date = 1 February 2014 }}</ref> Cautions include:<ref name="MSR">{{cite web | title = Gleevec (imatinib) dosing, indications, interactions, adverse effects, and more | work = Medscape Reference | publisher = WebMD | access-date = 24 January 2014 | url = http://reference.medscape.com/drug/gleevec-imatinib-342239#showall | url-status = live | archive-url = https://web.archive.org/web/20140103224530/http://reference.medscape.com/drug/gleevec-imatinib-342239#showall | archive-date = 3 January 2014 }}</ref> * Hepatic impairment * Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities * Pregnancy, risk of embryo-fetal toxicity * Risk of fluid retention * Risk of growth stunting in children or adolescents

==Side effects== [[File:Bcr abl STI 1IEP.png|right|thumb|bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).]]

The most common side effects include nausea, vomiting, diarrhea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite,<ref>{{cite web | title = Imatinib | url = http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Biologicaltherapies/Cancergrowthinhibitors/Imatinib.aspx#DynamicJumpMenuManager_6_Anchor_3 | work = Macmillan Cancer Support | access-date = 26 December 2012 | url-status = live | archive-url = https://web.archive.org/web/20121122103401/http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Biologicaltherapies/Cancergrowthinhibitors/Imatinib.aspx#DynamicJumpMenuManager_6_Anchor_3 | archive-date = 22 November 2012 }}</ref> weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), and edema.<ref name="AustriaCodex">{{cite book | veditors = Haberfeld H | title = Austria-Codex | location = Vienna | year = 2009 | publisher = Österreichischer Apothekerverlag | edition = 2009/2010 | isbn = 978-3-85200-196-8 | language = German }}</ref>

=== Cardiotoxicity === In some individuals, imatinib use was reported to be associated with left ventricular dysfunction which sometimes progressed to congestive cardiac failure despite an absence of prior heart disease. Clinical trials of imatinib did not report cardiac adverse effects, but had reported a notably high incidence of peripheral oedema (edema), with some cases classified as severe.<ref name="Kerkela_2006" />

Patient biopsies as well as mice treated with large doses of imatinib exhibited cellular signs of cardiotoxicity. Studies determined a potential pathway that led to cardiotoxicity, stemming from a stress response within the endoplasmic reticulum and the effects of c-ABL inhibition.<ref name="Mughal_2010">{{cite journal | vauthors = Mughal TI, Schrieber A | title = Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase | journal = Biologics: Targets & Therapy| volume = 4 | pages = 315–323 | date = December 2010 | pmid = 21209726 | pmc = 3010822 | doi = 10.2147/BTT.S5775 | doi-access = free }}</ref> Cardiotoxic effects appeared to mediated by inhibition of cytoplasmic ABL1 tyrosine kinase.<ref name="Kerkela_2006">{{cite journal | vauthors = Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T | title = Cardiotoxicity of the cancer therapeutic agent imatinib mesylate | journal = Nature Medicine | volume = 12 | issue = 8 | pages = 908–916 | date = August 2006 | pmid = 16862153 | doi = 10.1038/nm1446 | url = http://www.escholarship.org/uc/item/34r245fh | access-date = 16 August 2019 | url-status = live | s2cid = 9385835 | archive-url = https://web.archive.org/web/20200621012322/https://escholarship.org/uc/item/34r245fh | archive-date = 21 June 2020 }}</ref>

=== Childhood growth inhibition === Multiple human and animal studies suggest that if imatinib is used in prepubescent children, it may delay normal growth (more specifically bone elongation), although some may experience at least partial catch-up growth during puberty.<ref name="Shima_2011" />

The reason for this side effect is unclear; interference with a growth hormone (GH)-related pathway may be involved (prepubertal growth is GH-dependent, whereas pubertal growth is synergystically promoted by both GH and sex hormones).<ref name="Shima_2011">{{cite journal | vauthors = Shima H, Tokuyama M, Tanizawa A, Tono C, Hamamoto K, Muramatsu H, Watanabe A, Hotta N, Ito M, Kurosawa H, Kato K, Tsurusawa M, Horibe K, Shimada H | title = Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia | journal = The Journal of Pediatrics | volume = 159 | issue = 4 | pages = 676–681 | date = October 2011 | pmid = 21592517 | doi = 10.1016/j.jpeds.2011.03.046 }}</ref>

===Pigmentation changes=== Imatinib use may cause lightening/depigmentation or darkening/repigmentation of hair (as is the case with some other tyrosine kinase inhibitors) and/or skin as well as hyperpigmentation of the gingiva. The median onset of hair color change is 4 weeks after initiation of therapy (but may occur over a year after initiation), is dose-dependent, and is reversible upon treatment discontinuation or dose reduction.<ref name="Ricci_2016">{{cite journal | vauthors = Ricci F, De Simone C, Del Regno L, Peris K | title = Drug-induced hair colour changes | journal = European Journal of Dermatology | volume = 26 | issue = 6 | pages = 531–536 | date = December 2016 | pmid = 27545142 | doi = 10.1684/ejd.2016.2844 }}</ref>

C-kit receptors - one of the biological target of imatinib - are expressed by melanocytes.<ref name="Ricci_2016" />

=== Hepatotoxicity === Both mild and severe hepatotoxicity can occur. 5% of patients developed mild hepatotoxicity within the first 2 years of beginning treatment. However, severe hepatotoxicity is rare. Both severe and mild hepatotoxicity can be reversed by either stopping treatment or reducing the dosage of imatinib.<ref name="Mughal_2010" />

==Overdose== Medical experience with imatinib overdose is limited.<ref name="TGA">{{cite web | title = Glivec (imatinib) | date = 21 August 2013 | work = TGA eBusiness Services | publisher = Novartis Pharmaceuticals Australia Pty Ltd | access-date = 24 January 2014 | url = https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04296-3 | url-status = live | archive-url = https://web.archive.org/web/20170112064341/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04296-3 | archive-date = 12 January 2017 }}</ref> Treatment is supportive.<ref name="TGA" /> Imatinib is highly plasma protein-bound:<ref name="TGA" /> dialysis is unlikely to be helpful removing imatinib.

== Interactions ==

Its use is advised against in people on strong CYP3A4 inhibitors such as clarithromycin, chloramphenicol, ketoconazole, ritonavir and nefazodone due to its reliance on CYP3A4 for metabolism.<ref name="MSR" /> Likewise it is a CYP3A4, CYP2D6 and CYP2C9 inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs.<ref name="MSR" /> 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.<ref name="AustriaCodex" />

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.<ref name="Arzneimittel-Interaktionen">{{cite book | veditors = Klopp T | title = Arzneimittel-Interaktionen | year = 2010 | publisher = Arbeitsgemeinschaft für Pharmazeutische Information | edition = 2010/2011 | isbn = 978-3-85200-207-1 | language = German }}</ref>

Eating grapefruit and drinking grapefruit juice are strongly discouraged as it increases the concentration of imatinib in the blood.<ref>{{Cite web | title = Drugs and Supplements – Imatinib (Oral Route) | date = 1 April 2023 | website = Mayo Clinic | url = https://www.mayoclinic.org/drugs-supplements/imatinib-oral-route/proper-use/drg-20068331#:~:text=Do%20not%20eat%20grapefruit%20or,handle%20crushed%20or%20broken%20tablets | access-date = 7 April 2023 | archive-date = 7 April 2023 | archive-url = https://web.archive.org/web/20230407044955/https://www.mayoclinic.org/drugs-supplements/imatinib-oral-route/proper-use/drg-20068331#:~:text=Do%20not%20eat%20grapefruit%20or,handle%20crushed%20or%20broken%20tablets. | url-status = live }}</ref>

==Pharmacology== ===Mechanism of action=== right|Mechanism of action of imatinib {{Infobox drug mechanism| drug_name = Imatinib | Image = 1IEP.png | Alt = | Caption = Crystallographic structure of tyrosine-protein kinase ABL (rainbow colored, N-terminus = blue, C-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).<ref name="pmid12154025">{{PDB|1IEP}}; {{cite journal | vauthors = Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J | title = Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571) | journal = Cancer Research | volume = 62 | issue = 15 | pages = 4236–4243 | date = August 2002 | pmid = 12154025 | url = http://cancerres.aacrjournals.org/content/62/15/4236.full.pdf | access-date = 6 October 2013 | url-status = live | archive-url = https://web.archive.org/web/20210828123021/https://cancerres.aacrjournals.org/content/canres/62/15/4236.full.pdf | archive-date = 28 August 2021 }}</ref> | Use = chronic myelogenous leukemia | Biological_target = ABL, c-kit, PDGF-R | ATC_prefix = L01 | ATC_suffix = XE01 | MOA_text = Tyrosine-kinase inhibitor | PDB_ligand = STI | PDB_complex = 1iep | align = left }}

Imatinib is a 2-phenyl amino pyrimidine 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.<ref>{{cite book | vauthors = Takimoto CH, Calvo E | veditors = Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ | chapter = Principles of oncologic pharmacotherapy | title = Cancer Management: A Multidisciplinary Approach | location = Melville, New York | date = 2008 | publisher = PRR | chapter-url = http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | archive-url = https://web.archive.org/web/20090515221337/http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 | archive-date = 15 May 2009 | edition = 11th }}</ref> This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.<ref>{{cite journal | vauthors = Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L | title = Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias | journal = The Lancet. Oncology | volume = 4 | issue = 2 | pages = 75–85 | date = February 2003 | pmid = 12573349 | doi = 10.1016/S1470-2045(03)00979-3 }}</ref>

Imatinib is quite selective for ''bcr-abl'', though it does also inhibit other targets mentioned above (c-kit and PDGF-R), as well as ABL2 (ARG) and DDR1 tyrosine kinases and NQO2 – an oxidoreductase.<ref>{{cite journal | vauthors = Hantschel O, Rix U, Superti-Furga G | title = Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib | journal = Leukemia & Lymphoma | volume = 49 | issue = 4 | pages = 615–619 | date = April 2008 | pmid = 18398720 | doi = 10.1080/10428190801896103 | s2cid = 33895941 | url = http://infoscience.epfl.ch/record/164371 }}</ref> Imatinib also inhibits the ''abl'' protein of non-cancer cells, but these cells normally have additional redundant tyrosine kinases, which allows them to continue to function even if ''abl'' tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on ''bcr-abl''.<ref name="Deininger_2003">{{cite journal | vauthors = Deininger MW, Druker BJ | title = Specific targeted therapy of chronic myelogenous leukemia with imatinib | journal = Pharmacological Reviews | volume = 55 | issue = 3 | pages = 401–423 | date = September 2003 | pmid = 12869662 | doi = 10.1124/pr.55.3.4 | s2cid = 8620208 }}</ref> 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, leading to tumor cell death.<ref>{{cite journal | vauthors = Vigneri P, Wang JY | title = Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase | journal = Nature Medicine | volume = 7 | issue = 2 | pages = 228–234 | date = February 2001 | pmid = 11175855 | doi = 10.1038/84683 | s2cid = 40934433 }}</ref>

====Other pathways affected==== The Bcr-Abl pathway has many downstream pathways including<ref name="Weisberg_2007" /> * the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. * It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. * The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. * The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.<ref name="Weisberg_2007">{{cite journal | vauthors = Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD | title = Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia | journal = Nature Reviews. Cancer | volume = 7 | issue = 5 | pages = 345–356 | date = May 2007 | pmid = 17457302 | doi = 10.1038/nrc2126 | s2cid = 20640317 }}</ref>

===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 h and 40 h, 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.<ref>{{cite journal | vauthors = Scheinfeld N | title = A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases | journal = Journal of Drugs in Dermatology | volume = 5 | issue = 2 | pages = 117–122 | date = February 2006 | pmid = 16485879 }}</ref>

==Chemistry== ===Synthesis=== class=skin-invert-image|center|1200px

==History== Imatinib was invented in the early 1990s (the first patent application took place in 1994) by scientists at Ciba-Geigy (which merged with Sandoz in 1996 to become Novartis), in a team led by the British biochemist Nicholas Lydon and that included Elisabeth Buchdunger and Jürg Zimmermann,<ref name="Innovation">{{cite web | vauthors = Staff | title = The Story of Gleevec | work = Innovation.org (a project of the Pharmaceutical Research and Manufacturers of America) | url = http://www.innovation.org/index.cfm/StoriesofInnovation/InnovatorStories/The_Story_of_Gleevec | archive-url = https://web.archive.org/web/20131021011042/http://www.innovation.org/index.cfm/StoriesofInnovation/InnovatorStories/The_Story_of_Gleevec | archive-date = 21 October 2013 }}</ref> and its use to treat CML was driven by oncologist Brian Druker of Oregon Health & Science University (OHSU).<ref name="NYT 20091103">{{cite news | vauthors = Dreifus C | title = Researcher Behind the Drug Gleevec | date = 2 November 2009 | author-link = Claudia Dreifus | work = The New York Times | url = https://www.nytimes.com/2009/11/03/science/03conv.html | access-date = 16 February 2020 | archive-url = https://web.archive.org/web/20140114055940/http://www.nytimes.com/2009/11/03/science/03conv.html | archive-date = 14 January 2014 | url-status = live }}</ref> Other major contributions to imatinib development were made by biologist Anthony R. Hunter at Salk Institute for Biological Studies in La Jolla, California, Carlo Gambacorti-Passerini, a physician, scientist, and hematologist at the University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital in London, and later on by Charles Sawyers of Memorial Sloan Kettering Cancer Center in New York.<ref name="NYT 20091103" /><ref>{{cite journal | vauthors = Gambacorti-Passerini C | title = Part I: Milestones in personalised medicine--imatinib | journal = The Lancet. Oncology | volume = 9 | issue = 6 | pages = 600 | date = June 2008 | pmid = 18510992 | doi = 10.1016/S1470-2045(08)70152-9 | s2cid = 41907624 }}</ref>

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.<ref>{{cite journal | vauthors = Druker BJ, Lydon NB | title = Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia | journal = The Journal of Clinical Investigation | volume = 105 | issue = 1 | pages = 3–7 | date = January 2000 | pmid = 10619854 | pmc = 382593 | doi = 10.1172/JCI9083 }}</ref>

When Novartis tested imatinib in rats, mice, rabbits, dogs, and monkeys in 1996, it was found to have several toxic effects; in particular, results indicating liver damage in dogs nearly stopped drug development completely. However, favorable results in studies with monkeys and ''in vitro'' human cells allowed testing to continue in humans.<ref>{{cite journal | vauthors = Pippin JJ | title = Animal research in medical sciences: Seeking a convergence of science, medicine, and animal law | journal = S. Tex. L. Rev. | volume = 54 | year = 2012 | page = 469 | url = http://animalstudiesrepository.org/cgi/viewcontent.cgi?article=1013&context=acwp_all | url-status = live | archive-url = https://web.archive.org/web/20170918185556/http://animalstudiesrepository.org/cgi/viewcontent.cgi?article=1013&context=acwp_all | archive-date = 18 September 2017 }}.</ref><ref name="Monmaney 1999">{{cite web | vauthors = Monmaney T | title = A Triumph in the War Against Cancer | date = 3 December 1999 | website = Smithsonian | url = http://www.smithsonianmag.com/science-nature/a-triumph-in-the-war-against-cancer-1784705/ | access-date = 16 January 2017 | archive-date = 17 January 2017 | archive-url = https://web.archive.org/web/20170117111556/http://www.smithsonianmag.com/science-nature/a-triumph-in-the-war-against-cancer-1784705/ | url-status = live }}</ref><ref name="Li 2015 p. 81">{{cite book | vauthors = Li JJ | title = Top Drugs: History, Pharmacology, Syntheses | year = 2015 | publisher = Oxford University Press | isbn = 978-0-19-936259-2 | url = https://books.google.com/books?id=Dq3fCQAAQBAJ&pg=PA81 | page = 81 | url-status = live | archive-url = https://web.archive.org/web/20170918185556/https://books.google.com/books?id=Dq3fCQAAQBAJ&pg=PA81 | archive-date = 18 September 2017 }}</ref>

The first clinical trial of Gleevec took place in 1998, after Novartis reluctantly synthesized and released a few grams of the drug for Druker, enough for him to run a trial using a hundred or so patients.<ref>{{Cite book | vauthors = Siddhartha M | title = The Emperor of All Maladies | location = New York, NY | pages = [https://archive.org/details/emperorofallmala00mukh/page/436 436] | year = 2010 | publisher = Scribner | isbn = 978-1-4391-0795-9 | url-access = registration | url = https://archive.org/details/emperorofallmala00mukh/page/436 }}</ref> Mel Mann, who entered the clinical trial in August 1998, is the longest living person to be treated with the drug.<ref>{{Cite web | title = "The Miracle Drug" | date = October 2021 | url = https://media.curetoday.com/files/0vv8moc6/curetoday/95962af6a726a6b63a828fba63e22f992159d30c.pdf/CURE_HEM2_Cover_OCT2021-final.pdf | access-date = 8 April 2023 | archive-date = 3 July 2022 | archive-url = https://web.archive.org/web/20220703143244/https://media.curetoday.com/files/0vv8moc6/curetoday/95962af6a726a6b63a828fba63e22f992159d30c.pdf/CURE_HEM2_Cover_OCT2021-final.pdf | url-status = live }}</ref><ref>{{Cite web | title = World's Longest Living Gleevec CML Survivor Meets Physician Who Helped Develop the Drug | date = 22 September 2022 | url = https://mytomorrows.com/en/blog/worlds-longest-living-gleevec-cml-survivor-meets-physician-who-helped-develop-the-drug | access-date = 8 April 2023 | archive-date = 4 April 2023 | archive-url = https://web.archive.org/web/20230404162831/https://mytomorrows.com/en/blog/worlds-longest-living-gleevec-cml-survivor-meets-physician-who-helped-develop-the-drug | url-status = live }}</ref><ref>{{Cite web | title = Patient-Doctor Perspectives: Groundbreaking Research in CML | date = 22 September 2021 | url = https://thebloodline.org/TBL/100-e95/ | access-date = 8 April 2023 | archive-date = 5 April 2023 | archive-url = https://web.archive.org/web/20230405002349/https://thebloodline.org/TBL/100-e95/ | url-status = live }}</ref><ref>{{Cite web | title = 'Game-changer' cancer drug celebrates 20 years. Gleevec turned a death sentence into a chronic disease for many. | date = 10 May 2021 | website = USA Today | url = https://www.usatoday.com/in-depth/news/health/2021/05/10/life-saving-drug-gleevec-leukemia-other-cancers-20th-anniversary/5000025001/ | access-date = 8 April 2023 | archive-date = 5 April 2023 | archive-url = https://web.archive.org/web/20230405182622/https://www.usatoday.com/in-depth/news/health/2021/05/10/life-saving-drug-gleevec-leukemia-other-cancers-20th-anniversary/5000025001/ | url-status = live }}</ref><ref>{{Cite web | title = Offering Hope through Better Treatments and Care | date = 8 April 2023 | url = https://www.cancer.gov/news-events/nca50/stories/advances-in-treatment-and-care | access-date = 8 April 2023 | archive-date = 10 April 2023 | archive-url = https://web.archive.org/web/20230410201931/https://www.cancer.gov/news-events/nca50/stories/advances-in-treatment-and-care | url-status = live }}</ref> The drug received FDA approval in May 2001, only two and a half years after the new drug application was submitted.<ref name="Innovation" /><ref>Novartis press release, 10 May 2001. [https://archive.today/20131021105057/http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=5838 FDA approves Novartis' unique cancer medication Glivec]</ref> On the same month it made the cover of ''TIME'' magazine as a "bullet" to be used against 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".<ref name="NYT 20091103" />

During the FDA review, the tradename of the drug for the US market was changed from "Glivec" to "Gleevec" at the request of the FDA, to avoid confusion with Glyset, a diabetes drug.<ref name="Cohen_2002">{{cite journal | vauthors = Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, Benson K, Leighton J, Kim SK, Wood R, Rothmann M, Chen G, U KM, Staten AM, Pazdur R | title = Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia | journal = Clinical Cancer Research | volume = 8 | issue = 5 | pages = 935–942 | date = May 2002 | pmid = 12006504 | url = http://clincancerres.aacrjournals.org/content/8/5/935.long | access-date = 21 October 2013 | url-status = live | archive-url = https://web.archive.org/web/20120719012128/http://clincancerres.aacrjournals.org/content/8/5/935.long | archive-date = 19 July 2012 }}</ref><ref>{{cite web | vauthors = Fromer MJ | title = What's in a Name? Quite a Lot When It Comes to Marketing & Selling New Cancer Drugs | date = December 2002 | work = Oncology Times | url = http://www.brandinstitute.com/NEWS/ONCOLOGYTIMES_12_02.HTM | archive-url = https://web.archive.org/web/20131021122531/http://www.brandinstitute.com/NEWS/ONCOLOGYTIMES_12_02.HTM | archive-date = 21 October 2013 }}</ref><ref>{{cite web | title = Novartis Oncology Changes Trade Name of Investigational Agent Glivec to Gleevec in the United States | date = 30 April 2001 | work = Novartis Press Release | url = http://www.thefreelibrary.com/Novartis+Oncology+Changes+Trade+Name+of+Investigational+Agent...-a073818775 | archive-url = https://web.archive.org/web/20131021113926/http://www.thefreelibrary.com/Novartis+Oncology+Changes+Trade+Name+of+Investigational+Agent...-a073818775 | archive-date = 21 October 2013 }}</ref>

A Swiss patent application was filed on imatinib and various salts on in April 1992, which was then filed in the EU, the US, and other countries in March and April 1993.<ref name="US5521184">{{cite patent | country = US | number = 5,521,184 | url = https://patents.google.com/patent/US5521184A/en?oq=US5521184 | title = Pyrimidine derivatives and processes for the preparation thereof | gdate = 28 May 1996 | assign = Novartis Corp | inventor = Zimmermann J }}</ref><ref name="Patentfamily">{{cite web | title = Imatinib Patent Family | date = 1996 | url = http://worldwide.espacenet.com/publicationDetails/inpadocPatentFamily?CC=US&NR=5521184A&KC=A&FT=D&ND=3&date=19960528&DB=worldwide.espacenet.com&locale=en_EP | publisher = Espacenet | access-date = 23 July 2014 | archive-date = 20 September 2018 | archive-url = https://web.archive.org/web/20180920171840/https://worldwide.espacenet.com/publicationDetails/inpadocPatentFamily?CC=US&NR=5521184A&KC=A&FT=D&ND=3&date=19960528&DB=worldwide.espacenet.com&locale=en_EP | url-status = live }}</ref> and in 1996 United States and European patent offices issued patents listing Jürg Zimmermann as the inventor.<ref name="US5521184" /><ref name=EP0564409>{{Cite patent | country = EP | number = 0564409 | title = Pyrimidin derivatives and process for their preparation | assign = Novartis Corp | inventor = Zimmermann J | url = https://patents.google.com/patent/EP0564409B1/en?oq=EP0564409 }}</ref>

In July 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate (the mesylate salt of imatinib). The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. This is the actual form of the drug sold as Gleevec/Glivec; a salt (imatinib mesylate) as opposed to a free base, and the beta crystalline form as opposed to the alpha or other form.<ref>{{cite web | title = EMEA Scientific Discussion of Glivec | date = 2004 | work = European Medicines Agency | url = http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000406/WC500022203.pdf | archive-url = https://web.archive.org/web/20141105064353/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000406/WC500022203.pdf | archive-date = 5 November 2014 }}</ref>{{rp|3 and 4}} In 1998, Novartis filed international patent applications claiming priority to the 1997 filing.<ref>Note: The Indian patent application, which became the subject of litigation in India that gathered a lot of press, does not appear to be publicly available. However according to [https://www.scribd.com/doc/133340456/IPAB-Order-Dated-26-Jun-2009-in-Novartis-v-Union-of-India documents produced in the course of that litigation] {{webarchive|url=https://web.archive.org/web/20150716041227/https://www.scribd.com/doc/133340456/IPAB-Order-Dated-26-Jun-2009-in-Novartis-v-Union-of-India |date=16 July 2015 }} (page 27), "The Appellant's application under the PCT was substantially on the same invention as had been made in India."</ref><ref name="PCT">{{Cite patent | country = WO | number = 9903854 | url = https://patents.google.com/patent/WO1999003854A1/en?oq=WO9903854 | title = Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use | inventor = Zimmermann J, Sutter B, Bürger HM | assign = Novartis }}</ref> A United States patent was granted in 2005.<ref>{{cite patent | country = US | number = 6,894,051 | url = https://patents.google.com/patent/US6894051B1/en?oq=US6894051 | title = Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use | inventor = Zimmermann J, Sutter B, Bürger HM | assign = Novartis AG | gdate = 17 May 2005 }}</ref>

==Society and culture== ===Economics=== [[File:Glivec 400mg.jpg|thumb|A box of 400-milligram Glivec tablets (Novartis), as sold in Germany.]]

In 2013, more than 100 cancer specialists published a letter in ''Blood'' saying that the prices of many new cancer drugs, including imatinib, are so high that people in the United States could not afford them, and that the level of prices, and profits, was so high as to be immoral. Signatories of the letter included Brian Druker, Carlo Gambacorti-Passerini, and John Goldman, developers of imatinib.<ref>{{cite journal | vauthors = Abboud C, Berman E, Cohen A, Cortes J, DeAngelo D, Deininger M, etal | title = The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts | journal = Blood | volume = 121 | issue = 22 | pages = 4439–4442 | date = May 2013 | pmid = 23620577 | pmc = 4190613 | doi = 10.1182/blood-2013-03-490003 | url = http://bloodjournal.hematologylibrary.org/content/early/2013/04/23/blood-2013-03-490003.full.pdf+html | url-status = live | collaboration = Experts in Chronic Myeloid Leukemia | archive-date = 26 March 2014 | archive-url = https://web.archive.org/web/20140326114400/http://bloodjournal.hematologylibrary.org/content/early/2013/04/23/blood-2013-03-490003.full.pdf+html | hdl = 10281/222941 }}</ref><ref>{{cite news | vauthors = Pollack A | title = Doctors Denounce Cancer Drug Prices of $100,000 a Year | date = 25 April 2013 | work = The New York Times | url = https://www.nytimes.com/2013/04/26/business/cancer-physicians-attack-high-drug-costs.html | access-date = 16 February 2020 | archive-url = https://web.archive.org/web/20170221195459/http://www.nytimes.com/2013/04/26/business/cancer-physicians-attack-high-drug-costs.html | archive-date = 21 February 2017 }}</ref> They wrote that in 2001, imatinib was priced at {{US$|30000|2001|long=no}} a year, which was based on the price of interferon, then the standard treatment, and that at this price Novartis would have recouped its initial development costs in two years. They wrote that after unexpectedly becoming a blockbuster, Novartis increased the price to {{US$|92000|2012|long=no}} per year in 2012, with annual revenues of $4.7 billion. Other physicians have complained about the cost.<ref>{{cite journal | vauthors = Schiffer CA | title = BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia | journal = The New England Journal of Medicine | volume = 357 | issue = 3 | pages = 258–265 | date = July 2007 | pmid = 17634461 | doi = 10.1056/NEJMct071828 }}</ref><ref>{{cite news | vauthors = Pollack A | title = As Pills Treat Cancer, Insurance Lags Behind | date = 14 April 2009 | work = The New York Times | url = https://www.nytimes.com/2009/04/15/business/15pill.html | access-date = 16 February 2020 | archive-url = https://web.archive.org/web/20141102215810/http://www.nytimes.com/2009/04/15/business/15pill.html | archive-date = 2 November 2014 }}</ref><ref>{{cite news | vauthors = Brody JE | title = Living With a Formerly Fatal Blood Cancer | date = 18 January 2010 | work = The New York Times | url = https://www.nytimes.com/2010/01/19/health/19brod.html | access-date = 16 February 2020 | archive-url = https://web.archive.org/web/20170209082505/http://www.nytimes.com/2010/01/19/health/19brod.html | archive-date = 9 February 2017 }}</ref>

Druker, who led the clinical studies, never received any royalties or profits from the success of the drug.<ref>{{cite news | vauthors = Rosenthal E | title = Why Competition Won't Bring Down Drug Prices | date = 22 June 2018 | work = The New York Times | url = https://www.nytimes.com/2018/06/21/opinion/competition-drug-prices.html | access-date = 16 February 2020 | archive-date = 29 February 2020 | archive-url = https://web.archive.org/web/20200229033834/https://www.nytimes.com/2018/06/21/opinion/competition-drug-prices.html | url-status = live }}</ref>

By 2016, the average wholesale price had increased to {{US$|120000|2016|long=no}} a year, according to an analysis prepared for ''The Washington Post'' by Stacie Dusetzina of the University of North Carolina at Chapel Hill. When competitive drugs came on the market, they were sold at a higher price to reflect the smaller population,{{clarify|date=November 2017}} and Novartis raised the price of Gleevec to match them.<ref>{{cite news | title = This drug is defying a rare form of leukemia – and it keeps getting pricier | date = 9 March 2016 | url = https://www.washingtonpost.com/business/this-drug-is-defying-a-rare-form-of-leukemia--and-it-keeps-getting-pricier/2016/03/09/4fff8102-c571-11e5-a4aa-f25866ba0dc6_story.html | newspaper = The Washington Post | access-date = 10 March 2016 | url-status = live | archive-url = https://web.archive.org/web/20160310135532/https://www.washingtonpost.com/business/this-drug-is-defying-a-rare-form-of-leukemia--and-it-keeps-getting-pricier/2016/03/09/4fff8102-c571-11e5-a4aa-f25866ba0dc6_story.html | archive-date = 10 March 2016 }}</ref>

A 2012 economic analysis funded by Bristol-Myers Squibb estimated that the discovery and development of imatinib and related drugs had created $143 billion in societal value at a cost to consumers of approximately $14 billion. The $143 billion figure was based on an estimated 7.5 to 17.5 year survival advantage conferred by imatinib treatment, and included the value (discounted at 3% per annum) of ongoing benefits to society after the imatinib patent expiration.<ref>{{cite journal | vauthors = Yin W, Penrod JR, Maclean R, Lakdawalla DN, Philipson T | title = Value of survival gains in chronic myeloid leukemia | journal = The American Journal of Managed Care | volume = 18 | issue = 11 Suppl | pages = S257–S264 | date = November 2012 | pmid = 23327457 | url = http://www.ajmc.com/journals/supplement/2012/A386_12nov_Oncology/A386_12nov_Onclogy_Yin_S257to64/ | url-status = live | archive-url = https://web.archive.org/web/20150724000812/http://www.ajmc.com/journals/supplement/2012/A386_12nov_Oncology/A386_12nov_Onclogy_Yin_S257to64/ | archive-date = 24 July 2015 }}</ref>

Prices for a 100 mg pill of Gleevec internationally range from $20 to $30,<ref>{{cite web | title = Report on New Patented Drugs – Gleevec | location = Canada | url = http://www.pmprb-cepmb.gc.ca/english/View.asp?x=529&mp=572 | author = Patented Medicine Review Board | archive-url = https://web.archive.org/web/20110706181917/http://www.pmprb-cepmb.gc.ca/english/View.asp?x=529&mp=572 | archive-date = 6 July 2011 }}</ref> although generic imatinib is cheaper, as low as $2 per pill.<ref>{{cite web | title = pharmacychecker.com | url = http://www.pharmacychecker.com/listing.asp?criteria_2=imatinib&Search=1&x=51&y=14 | publisher = pharmacychecker.com | access-date = 3 April 2013 | url-status = live | archive-url = https://web.archive.org/web/20140202125936/http://www.pharmacychecker.com/listing.asp?criteria_2=imatinib&Search=1&x=51&y=14 | archive-date = 2 February 2014 }}</ref>

===Controversies=== ====Patent litigation in India==== {{Main|Novartis v. Union of India & Others}}

Novartis fought a seven-year, controversial battle to patent Gleevec in India, and took the case all the way to the Indian Supreme Court. The patent application at the center of the case was filed by Novartis in India in 1998, after India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement. As part of this agreement, India made changes to its patent law, the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions. These changes came into effect in 2005, so Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law in 2005, just before the laws came into effect.<ref name="Harris_2013">{{cite news | vauthors = Harris G, Thomas K | title = Low-Cost Drugs in Poor Nations Get a Lift in Indian Court | date = 1 April 2013 | work = The New York Times | url = https://www.nytimes.com/2013/04/02/business/global/top-court-in-india-rejects-novartis-drug-patent.html | access-date = 16 February 2020 | archive-url = https://web.archive.org/web/20141220194654/http://www.nytimes.com/2013/04/02/business/global/top-court-in-india-rejects-novartis-drug-patent.html | archive-date = 20 December 2014 }}</ref><ref>{{cite news | title = The Novartis Patent Case: The Full Supreme Court Ruling | date = 1 April 2013 | work = The New York Times | url = https://india.blogs.nytimes.com/2013/04/01/the-novartis-patent-case-the-full-supreme-court-ruling/ | access-date = 16 February 2020 | archive-date = 30 September 2019 | archive-url = https://web.archive.org/web/20190930193427/https://india.blogs.nytimes.com/2013/04/01/the-novartis-patent-case-the-full-supreme-court-ruling/ | url-status = live }}</ref>

The patent application<ref name="PCT" /><ref>Note: The Indian patent application No.1602/MAS/1998 does not appear to be publicly available. However according to [https://www.scribd.com/doc/133340456/IPAB-Order-Dated-26-Jun-2009-in-Novartis-v-Union-of-India the decision of the IPAB on 26 June 2009] {{webarchive|url=https://web.archive.org/web/20150716041227/https://www.scribd.com/doc/133340456/IPAB-Order-Dated-26-Jun-2009-in-Novartis-v-Union-of-India |date=16 July 2015 }} (page 27) discussed below, "The Appellant's application under the PCT was substantially on the same invention as had been made in India."</ref> claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate).<ref>Staff, European Medicines Agency, 2004. [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000406/WC500022203.pdf EMEA Scientific Discussion of Glivec] {{webarchive|url=https://web.archive.org/web/20141105064353/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000406/WC500022203.pdf |date=5 November 2014 }}</ref>{{rp|3}} In 1993, during the time India did not allow patents on products, Novartis had patented imatinib, with salts vaguely specified, in many countries but could not patent it in India.<ref name="US5521184" /><ref name="EP0564409" /> The key differences between the two patent applications, were that 1998 patent application specified the counterion (Gleevec is a specific salt – imatinib mesylate) while the 1993 patent application did not claim any specific salts nor did it mention mesylate, and the 1998 patent application specified the solid form of Gleevec – the way the individual molecules are packed together into a solid when the drug itself is manufactured (this is separate from processes by which the drug itself is formulated into pills or capsules) – while the 1993 patent application did not. The solid form of imatinib mesylate in Gleevec is beta crystalline.<ref>[http://judis.nic.in/supremecourt/imgs1.aspx?filename=40212 Indian Supreme Court Decision] {{webarchive|url=https://web.archive.org/web/20130706085312/http://judis.nic.in/supremecourt/imgs1.aspx?filename=40212 |date=6 July 2013 }} paragraphs 5–6</ref>

As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR was granted in November 2003.<ref name="Decision8-9">[http://judis.nic.in/supremecourt/imgs1.aspx?filename=40212 Novartis v UoI, para 8–9] {{webarchive|url=https://web.archive.org/web/20130706085312/http://judis.nic.in/supremecourt/imgs1.aspx?filename=40212 |date=6 July 2013 }}</ref> Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India.<ref name="Basheer_2006" /><ref name=WSJ>{{cite web | vauthors = Krishna RJ, Whalen J | title = Novartis Loses Glivec Patent Battle in India | date = 1 April 2013 | work = Wall Street Journal | url = https://www.wsj.com/news/articles/SB10001424127887323296504578395672582230106 | archive-url = https://web.archive.org/web/20160529152242/http://www.wsj.com/news/articles/SB10001424127887323296504578395672582230106 | archive-date = 29 May 2016 }}</ref>

When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy."<ref name="Basheer_2006">{{cite web | vauthors = Basheer S | title = First Mailbox Opposition (Gleevec) Decided in India | date = 11 March 2006 | work = Spicy IP | url = http://spicyip.com/2006/03/first-mailbox-opposition-gleevec.html | archive-url = https://web.archive.org/web/20131021162820/http://spicyip.com/2006/03/first-mailbox-opposition-gleevec.html | archive-date = 21 October 2013 }}</ref><ref name="Appellate">{{cite web | title = Intellectual Property Appellate Board decision | date = 26 June 2009 | url = https://www.scribd.com/doc/133340456/IPAB-Order-Dated-26-Jun-2009-in-Novartis-v-Union-of-India | page = 149 | archive-url = https://web.archive.org/web/20150716041227/https://www.scribd.com/doc/133340456/IPAB-Order-Dated-26-Jun-2009-in-Novartis-v-Union-of-India | archive-date = 16 July 2015 }}</ref> At one point, Novartis went to court to try to invalidate Section 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal.<ref name="2007Decn">{{cite web | title = W.P. No.24759 of 2006 | date = 6 August 2007 | url = http://judis.nic.in/judis_chennai/qrydispfree.aspx?filename=11121 | work = The High Courst of Judicature at Madras | archive-url = https://web.archive.org/web/20131020071414/http://judis.nic.in/judis_chennai/qrydispfree.aspx?filename=11121 | archive-date = 20 October 2013 }}</ref> Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.

The Supreme Court case hinged on the interpretation of Section 3d. The Supreme Court issued its decision in 2013, ruling that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.<ref>{{cite web | title = Supreme Court rejects bid by Novartis to patent Glivec | url = http://spicyipindia.blogspot.co.uk/2013/04/supreme-court-rejects-bid-by-novartis.html | url-status = live | archive-url = https://web.archive.org/web/20131217091420/http://spicyipindia.blogspot.co.uk/2013/04/supreme-court-rejects-bid-by-novartis.html | archive-date = 17 December 2013 }}</ref>

==Research== One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-KIT.<ref>{{cite journal | vauthors = Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL | title = Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial | journal = Cancer | volume = 107 | issue = 2 | pages = 345–351 | date = July 2006 | pmid = 16779792 | doi = 10.1002/cncr.21996 | s2cid = 41124956 | doi-access = free }}</ref> However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-KIT is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-KIT. 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.

Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension. It was shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.<ref>{{cite journal | vauthors = Tapper EB, Knowles D, Heffron T, Lawrence EC, Csete M | title = Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition | journal = Transplantation Proceedings | volume = 41 | issue = 5 | pages = 1969–1971 | date = June 2009 | pmid = 19545770 | doi = 10.1016/j.transproceed.2009.02.100 }}</ref> However, a long-term trial of Imatinib in people with pulmonary arterial hypertension was unsuccessful, and serious and unexpected adverse events were frequent. These included 6 subdural hematomas and 17 deaths during or within 30 days of study end.<ref>{{cite journal | vauthors = Frost AE, Barst RJ, Hoeper MM, Chang HJ, Frantz RP, Fukumoto Y, Galié N, Hassoun PM, Klose H, Matsubara H, Morrell NW, Peacock AJ, Pfeifer M, Simonneau G, Tapson VF, Torres F, Dario Vizza C, Lawrence D, Yang W, Felser JM, Quinn DA, Ghofrani HA | title = Long-term safety and efficacy of imatinib in pulmonary arterial hypertension | journal = The Journal of Heart and Lung Transplantation | volume = 34 | issue = 11 | pages = 1366–1375 | date = November 2015 | pmid = 26210752 | doi = 10.1016/j.healun.2015.05.025 | hdl-access = free | doi-access = free | hdl = 11573/901480 }}</ref>

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<ref>{{cite journal | vauthors = Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J | title = LRP: role in vascular wall integrity and protection from atherosclerosis | journal = Science | volume = 300 | issue = 5617 | pages = 329–332 | date = April 2003 | pmid = 12690199 | doi = 10.1126/science.1082095 | s2cid = 2070128 | bibcode = 2003Sci...300..329B }}</ref> or with diabetes.<ref name="Lassila_2004">{{cite journal | vauthors = Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, Cooper ME | title = Imatinib attenuates diabetes-associated atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 5 | pages = 935–942 | date = May 2004 | pmid = 14988091 | doi = 10.1161/01.ATV.0000124105.39900.db | doi-access = free }}</ref>

Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.<ref name="Reeves_2005">{{cite journal | vauthors = Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D | title = Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases | journal = Nature Medicine | volume = 11 | issue = 7 | pages = 731–739 | date = July 2005 | pmid = 15980865 | doi = 10.1038/nm1265 | s2cid = 28325503 }}</ref>

''In vitro'' studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP). GSAP selectively increases the production and accumulation of neurotoxic beta-amyloid plaques, which suggests that molecules which target GSAP and are able to cross blood–brain barrier are potential therapeutic agents for treating Alzheimer's disease.<ref name="He_2010">{{cite journal | vauthors = He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P | title = Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease | journal = Nature | volume = 467 | issue = 7311 | pages = 95–98 | date = September 2010 | pmid = 20811458 | pmc = 2936959 | doi = 10.1038/nature09325 | bibcode = 2010Natur.467...95H }}</ref> 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.<ref>{{cite web | title = Alzheimer's may start in liver – Health – Alzheimer's Disease | date = 8 March 2011 | url = http://www.nbcnews.com/id/41971124 | publisher = NBC News | access-date = 6 January 2013 }}{{dead link|date=August 2024|bot=medic}}{{cbignore|bot=medic}}</ref> 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.<ref name="Holmes_2008">{{cite journal | vauthors = Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA | title = Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial | journal = Lancet | volume = 372 | issue = 9634 | pages = 216–223 | date = July 2008 | pmid = 18640458 | doi = 10.1016/S0140-6736(08)61075-2 | s2cid = 18340153 }}</ref>

A formulation of imatinib with a cyclodextrin (Captisol) as a carrier to overcome the blood–brain barrier has shown reversal of opioid tolerance in a 2012 study in rats.<ref>{{cite web | title = Eliminating Morphine Tolerance – Reformulated Imatinib | location = London | date = 23 February 2012 | url = http://www.medicalnewstoday.com/articles/242064.php | archive-url = https://web.archive.org/web/20130329203539/http://www.medicalnewstoday.com/articles/242064.php | archive-date = 29 March 2013 | work = Medical News Today | publisher = MediLexicon International Ltd }}</ref>

Imatinib is an experimental drug in the treatment of desmoid tumor or aggressive fibromatosis.<ref name="Kasper_2017">{{cite journal | vauthors = Kasper B, Baumgarten C, Garcia J, Bonvalot S, Haas R, Haller F, Hohenberger P, Penel N, Messiou C, van der Graaf WT, Gronchi A | title = An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) | journal = Annals of Oncology | volume = 28 | issue = 10 | pages = 2399–2408 | date = October 2017 | pmid = 28961825 | pmc = 5834048 | doi = 10.1093/annonc/mdx323 }}</ref>

Imatinib has also been investigated as a potential therapy for Duchenne-Meryon muscular dystrophy. In early ''mdx'' mouse research, imatinib was shown to decrease inflammation, muscle necrosis, and fibrosis while increasing grip strength.<ref>{{cite journal | vauthors = Huang P, Zhao XS, Fields M, Ransohoff RM, Zhou L | title = Imatinib attenuates skeletal muscle dystrophy in mdx mice | journal = FASEB Journal | volume = 23 | issue = 8 | pages = 2539–2548 | date = August 2009 | pmid = 19289603 | pmc = 2717779 | doi = 10.1096/fj.09-129833 | doi-access = free }}</ref>

==Etymology== The ''-tinib'' word stem makes reference to the drug's action as a tyrosine kinase (TYK) inhibitor.<ref>{{cite journal | vauthors = Karet GB | title = How Do Drugs Get Named? | journal = AMA Journal of Ethics | volume = 21 | issue = 8 | pages = E686–E696 | date = August 2019 | pmid = 31397664 | doi = 10.1001/amajethics.2019.686 | s2cid = 199507857 | doi-access = free }}</ref>

== References == {{Reflist}}

== External links == * {{cite web | title = Imatinib mesylate | date = 5 October 2006 | website = National Cancer Institute | url = https://www.cancer.gov/about-cancer/treatment/drugs/imatinibmesylate }}

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