imatinib imatinib 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. imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kinases such as csf1r, abl, c-kit, flt3, and pdgfr-β. specifically, it is used for chronic myelogenous leukemia (cml) and acute lymphocytic leukemia (all) that are philadelphia chromosome–positive (ph+), certain types of gastrointestinal stromal tumors (gist), hypereosinophilic syndrome (hes), chronic eosinophilic leukemia (cel), systemic mastocytosis, and myelodysplastic syndrome. imatinibclinical datatrade namesgleevec, glivec, othersother namessti-571ahfs/drugs.commonographmedlineplusa606018license data eu ema: by inn us dailymed: imatinib us fda: imatinib pregnancycategory au: d routes ofadministrationby mouthdrug classtyrosine kinase inhibitoratc codel01ea01 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only eu: rx-only pharmacokinetic databioavailability98%protein binding95%metabolismliver (mainly cyp3a4-mediated)elimination half-life18 h (imatinib)40 h (active metabolite)excretionfecal (68%) and kidney (13%)identifiers iupac name 4--n-(4-methyl-3-phenyl)benzamide cas number152459-95-5 y 220127-57-1 (mesilate)pubchem cid5291iuphar/bps5687drugbankdb00619 ychemspider5101 yuniibkj8m8g5hikeggd08066 ychebichebi:45783 ychemblchembl941 ypdb ligandsti (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid3037125 echa infocard100.122.739 chemical and physical dataformulac29h31n7omolar mass493.615 g·mol−13d model (jsmol)interactive image smiles cc1ccc(cc1nc2nccc(n2)c3cccnc3)nc(=o)c4ccc(cc4)cn5ccn(cc5)c inchi inchi=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) ykey:ktufnokkbvmgrw-uhfffaoysa-n y (verify) 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. imatinib was approved for medical use in the united states in 2001. it is on the world health organization's list of essential medicines. a generic version became available in the uk as of 2017. 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). 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. it's important to note that 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. note: it is not a cure, it is an effective way to control and prevent the disease from progressing. 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, and newly diagnosed. 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, to 70% in 2016. 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. 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. the drug is also approved in unresectable kit-positive gists. dermatofibrosarcoma protuberans (dfsp) the fda granted approval for the treatment of dermatofibrosarcoma protuberans (dfsp) patients in 2006. 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. on 25 january 2013, gleevec was approved for use in children with ph+ all. 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. according to a small trial, imatinib is an effective drug in some patients with aggressive fibromatosis. contraindications and cautions the only known contraindication to imatinib is hypersensitivity to imatinib. cautions include: 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 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; weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), and edema. although rare, restoration of hair color has been reported as well. 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. if imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty. overdose medical experience with imatinib overdose is limited. treatment is supportive. imatinib is highly plasma protein-bound: 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. 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. 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. 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. eating grapefruit is strongly discourage as it increases the concentration of imatinib in the blood. pharmacology mechanism of action mechanism of action of imatinib imatinibdrug mechanismcrystallographic structure of tyrosine-protein kinase abl (rainbow colored, n-terminus = blue, c-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).therapeutic usechronic myelogenous leukemiabiological targetabl, c-kit, pdgf-rmechanism of actiontyrosine-kinase inhibitor