Imatinib

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Glivec
)

Imatinib
Ball-and-stick model of the imatinib molecule
Clinical data
Trade namesGleevec, Glivec, others
Other namesSTI-571
AHFS/Drugs.comMonograph
MedlinePlusa606018
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classTyrosine kinase inhibitor[2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability98%
Protein binding95%
MetabolismLiver (mainly CYP3A4-mediated)
Elimination half-life18 h (imatinib)
40 h (active metabolite)
ExcretionFecal (68%) and kidney (13%)
Identifiers
  • 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide
JSmol)
  • Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)NC(=O)c4ccc(cc4)CN5CCN(CC5)C
  • 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) checkY
  • Key:KTUFNOKKBVMGRW-UHFFFAOYSA-N checkY
  (verify)

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by

systemic mastocytosis, and myelodysplastic syndrome.[2]

Common side effects include vomiting, diarrhea, muscle pain, headache, and rash.

liver problems, and heart failure.[2] Use during pregnancy may result in harm to the baby.[2] Imatinib works by stopping the Bcr-Abl tyrosine-kinase.[2] This can slow growth or result in programmed cell death of certain types of cancer cells.[2]

Imatinib was approved for medical use in the United States in 2001.[2] It is on the World Health Organization's List of Essential Medicines.[6] A generic version became available in the UK as of 2017.[7]

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).[8]

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, and newly diagnosed.[9]

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,[10] to 70% in 2016.[11] By 2023, the five year survival rate for people with chronic myeloid leukemia had risen to 90%.[12] 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.[13]

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.[14] The drug is also approved in unresectable KIT-positive GISTs.[9]

Dermatofibrosarcoma protuberans (DFSP)

The FDA granted approval for the treatment of dermatofibrosarcoma protuberans (DFSP) patients in 2006.[8] 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

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.[9] On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.[15]

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.[16][17][18][19] According to a small trial, imatinib is an effective drug in some patients with aggressive fibromatosis.[20]

Contraindications and cautions

The only known contraindication to imatinib is hypersensitivity to imatinib.[21] Cautions include:[22]

  • 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;[23] weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), and edema.[24] Although rare, restoration of hair color has been reported as well.[25][26] Severe

myocardium.[27]

If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.[28]

Overdose

Medical experience with imatinib overdose is limited.[29] Treatment is supportive.[29] Imatinib is highly plasma protein-bound:[29] dialysis is unlikely to be helpful removing imatinib.

Interactions

Its use is advised against in people on strong

levothyroxin via an unknown mechanism.[24]

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.[30]

Eating grapefruit and drinking grapefruit juice are strongly discouraged as it increases the concentration of imatinib in the blood.[31]

Pharmacology

Mechanism of action

Mechanism of action of imatinib
Mechanism of action of imatinib
Imatinib
Drug mechanism
Tyrosine-kinase inhibitor
External links
ATC codeL01XE01
PDB ligand idSTI: PDBe, RCSB PDB
LIGPLOT1iep

Imatinib is a 2-

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

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

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.[33] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[34]

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.[35] 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.[36] 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.[37]

Other pathways affected

The Bcr-Abl pathway has many downstream pathways including[38]

  • 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
    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.[38]

Pharmacokinetics

Imatinib is rapidly absorbed when given by mouth, and is highly

mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.[39]

Chemistry

Synthesis

History

Imatinib was invented in the late 1990s by scientists at

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.[41][42]

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.[43]

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.[44][45][46]

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.

Lasker-DeBakey Clinical Medical Research Award in 2009 for "converting a fatal cancer into a manageable chronic condition".[41]

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.[54][55][56]

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.

United States and European patent offices issued patents listing Jürg Zimmermann as the inventor.[57][59]

In July 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib

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.[60]: 3 and 4  In 1998, Novartis filed international patent applications claiming priority to the 1997 filing.[61][62] A United States patent was granted in 2005.[63]

Society and culture

Economics

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.[64][65] They wrote that in 2001, imatinib was priced at $30,000 (equivalent to $51,622 in 2023) 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 $92,000 (equivalent to $122,098 in 2023) per year in 2012, with annual revenues of $4.7 billion. Other physicians have complained about the cost.[66][67][68]

Druker, who led the clinical studies, never received any royalties or profits from the success of the drug.[69]

By 2016, the average wholesale price had increased to $120,000 (equivalent to $152,346 in 2023) 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,[clarification needed] and Novartis raised the price of Gleevec to match them.[70]

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.[71]

Prices for a 100 mg pill of Gleevec internationally range from $20 to $30,[72] although generic imatinib is cheaper, as low as $2 per pill.[73]

Controversies

Patent litigation in India

Main article: Novartis v. Union of India & Others

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.[74][75]

The patent application[62][76] claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate).[77]: 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.[57][59] 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.[78]

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.[79] Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India.[80][81]

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."[80][82] 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.[83] 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.[84]

Research

One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-KIT.[85] 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 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.[87]

In

diabetes.[89]

Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[90]

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.[91] 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.[92] 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.[93]

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.[94]

Imatinib is an experimental drug in the treatment of

desmoid tumor or aggressive fibromatosis.[95]

Etymology

The -tinib word stem makes reference to the drug's action as a tyrosine kinase (TYK) inhibitor.[96]

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  89. PMID 14988091
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  96. S2CID 199507857
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External links
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