Imatinib

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Key Terms: CYP3A4, Enzyme, Kinase, Leukemia, Tumor.

Definition

Imatinib mesylate is an enzyme inhibitor used for cancer therapy. Imatinib mesylate is also known as STI571 and is sold under the brand name, Gleevec. It was given the name STI571 during early development. STI stands for signal transduction inhibitor.

Purpose

Imatinib mesylate is approved by the U. S. Food and Drug Administration to treat a rare cancer called chronic myeloid leukemia (CML). (CML is also called chronic myelogenous leukemia or chronic myelocytic leukemia, as well.)

Description

Imatinib mesylate is the first drug of its kind developed. It fights cancer by turning off an enzyme called tyrosine kinase that causes CML cells to lose their ability to die so they can multiply at an abnormal rate. Its function is different from other cancer drugs because it specifically targets an enzyme that allows the growth of CML cells. This drug has been shown to significantly reduce the number of cancer cells in the blood and bone marrow of treated patients.

Patients who are diagnosed with CML in the three phases of disease can be treated with imatinib mesylate. Chronic myeloid leukemia appears to respond within one to three months following administration of this drug.

Recommended Dosage

A doctor experienced in the treatment of patients with CML should initiate therapy.

To minimize the risk of gastrointestinal irritation, imatinib mesylate should be taken with food and a large glass of water. The recommended dosage varies according to clinical circumstances and phase of disease, but generally ranges between 300 and 600 mg per day. As long as the patient continues to benefit, treatment should be continued.

Precautions

Studies have not been performed with imatinib mesylate to determine if it is a carcinogen (cancer causing); therefore it is not known whether this drug may cause mutations or may have cancer-causing effects. In addition, imatinib mesylate's safety and effectiveness has not been established in pediatric patients.

• Fluid retention and edema. If patients experience swelling or weight gain from water retention, they should inform their doctor and should be closely monitored. Signs and symptoms of fluid retention should be closely monitored and patients should be weighed regularly. Appropriate treatment must be provided if an unexpected rapid weight gain occurs. The likelihood of edema is increased with higher doses and in those over age 65 years.
• gastrointestinal irritation
• hematologic toxicity (toxicity of the blood)
• hepatotoxicity (toxicity of the liver)
• toxicities from long-term use

Side Effects

Commonly reported side effects include nausea and vomiting, muscle cramps, edema (water retention), skin rash, diarrhea, heartburn, and headache. Serious side effects occur less frequently, but if they occur may include severe edema liver toxicity, and the potential for bleeding especially in the elderly.

Interactions

Imatinib mesylate interacts with many other drugs. In some cases, side effects may be increased because imatinib mesylate might increase blood levels of certain drugs. Alternatively, imatinib mesylate may decrease blood levels of the drugs, thus reducing their effectiveness. In addition, the blood levels of imatinib mesylate may rise or fall because of other drugs. Therefore, side effects of imatinib mesylate may be increased or effectiveness may be reduced. The patient must discuss all of their medications with their doctor due to many potential drug-drug interactions.

CYP3A4 is an enzyme that is predominately responsible for the metabolism of imatinib mesylate. The following drugs or families of drugs may interact with imatinib mesylate:

• Inhibitors of the CYP3A4 family, such as ketoconazole, itraconazole, erythromycin.
• Co-medications that induce CYP3A4, such as dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John's Wort). No formal studies have been conducted on these medications and imatinib mesylate together.
• CYP3A4 substrates, such as cyclosporine or pimozide.
• CYP3A4 metabolized drugs, such as certain HMG-CoA reductase inhibitors, triazolo-benzodiazepines, and dihydropyridine calcium channel blockers.
• Warfarin. Patients needing anticoagulant therapy while taking imatinib mesylate should be prescribed lowmolecular weight or standard heparin. This list is not all-inclusive of all possible interactions. Patients must inform their doctors of any drugs they are taking in order to avoid drug interactions.

Investigators also evaluated the effect of St. John's wort, an herb used to treat mild to moderate depression, on the pharmacokinetics of imatinib. Studies showed that the administration of St. John's wort along with imatinib mesylate reduced absorption and increased elimination of imatinib, reducing drug exposure by as much as 42%. Since clinical efficacy of imatinib is dependent on drug dose and concentration, the interaction with St. John's wort could result in a loss of therapeutic effect. Therefore, the concurrent use of St. John's wort and imatinib should be avoided.

—Crystal Heather Kaczkowski, MSc.

Brand names: Gleevec®

Chemical formula:

Drug Forms:
• Imatinib Mesylate Oral tablet (below)
• Imatinib, STI-571 tablets

Español:
• Mesilato de imatinib, Tableta oral
• Tabletas de imatinib, STI-571

Imatinib Mesylate Oral tablet

What is this medicine?

IMATINIB is a chemotherapy drug. It targets a specific protein within cancer cells and stops the cancer cells from growing. It is used to treat certain leukemias, myelodysplastic syndromes, and other cancers. It is also used to treat specific digestive tract tumors called GISTs.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•bleeding problems
•infection (especially a virus infection such as chickenpox, cold sores, or herpes)
•heart disease
•heart failure
•kidney disease
•liver disease
•lung disease
•stomach problems
•an unusual or allergic reaction to imatinib, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

Take this medicine by mouth with a glass of water. Take it with food to decrease the chance of it upsetting your stomach. Follow the directions on the prescription label. Take your medicine at regular intervals. Do not take it more often than directed. Do not stop taking except on your doctor's advice.

If you have difficulty swallowing the tablets, let your doctor, pharmacist, or health care professional know. They can help you with advice.

Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for children as young as 2 years for selected conditions, precautions do apply.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

•antiviral medicines for HIV or AIDS
•bosentan
•cisapride
•clarithromycin
•cyclosporine
•dexamethasone
•diltiazem
•ergot alkaloids like dihydroergotamine, ergonovine, ergotamine, methylergonovine
•erythromycin
•grapefruit or grapefruit juice
•medicines for cholesterol like atorvastatin lovastatin, simvastatin
•medicines for depression, anxiety, or psychotic disturbances
•medicines for fungal infections like ketoconazole and itraconazole
•medicines for irregular heart beat like amiodarone, bepridil, dofetilide, encainide, flecainide, propafenone, quinidine
•medicines for seizures like carbamazepine, phenobarbital, phenytoin
•medicines for sleep
•NSAIDS, medicines for pain and inflammation, like ibuprofen or naproxen
•pimozide
•rifabutin
•rifampin
•sildenafil
•sirolimus
•St. John's wort
•tacrolimus
•vaccines
•verapamil
•warfarin

Talk to your doctor or health care professional before taking any of these medicines:
•acetaminophen
•aspirin
•ibuprofen
•ketoprofen
•naproxen

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Visit your doctor for checks on your progress. You will need to have regular blood tests while on this medicine. Report any new symptoms promptly.

Call your doctor or health care professional for advice if you get a fever, chills or sore throat, or other symptoms of a cold or flu. Do not treat yourself. This drug decreases your body's ability to fight infections. Try to avoid being around people who are sick.

This medicine may increase your risk to bruise or bleed. Call your doctor or health care professional if you notice any unusual bleeding.

Be careful brushing and flossing your teeth or using a toothpick because you may get an infection or bleed more easily. If you have any dental work done, tell your dentist you are receiving this medicine.

Avoid taking products that contain aspirin, acetaminophen, ibuprofen, naproxen, or ketoprofen unless instructed by your doctor. These medicines may hide a fever.

Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Men should inform their doctors if they wish to father a child. This medicine may lower sperm counts. Talk to your health care professional or pharmacist for more information. Do not breast-feed an infant while taking this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•low blood counts - this medicine may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding.
•signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine
•signs of decreased platelets or bleeding - bruising, pinpoint red spots on the skin, black, tarry stools, blood in the urine, nosebleeds
•signs of decreased red blood cells - unusually weak or tired, fainting spells, lightheadedness
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•breathing problems
•changes in vision
•dark urine
•general ill feeling or flu-like symptoms
•light-colored stools
•loss of appetite
•mouth sores
•redness, blistering, peeling or loosening of the skin, including inside the mouth
•right upper belly pain
•swelling of the legs or ankles
•trouble passing urine or change in the amount of urine
•vomiting
•yellowing of the eyes or skin

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•decreased appetite
•diarrhea
•difficulty sleeping
•headache
•heartburn
•joint pain
•muscle cramps or pain
•nausea
•upset stomach

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of reach of children.

Store tablets at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Protect from moisture. Keep tightly closed. Throw away any unused medicine after the expiration date.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Imatinib
Systematic (IUPAC) name
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
Identifiers
CAS number	152459-95-5 220127-57-1 (mesilate)
ATC code	L01XE01
PubChem	5291
DrugBank	APRD01028
ChemSpider	5101
Chemical data
Formula	C29H31N7O
Mol. mass	493.603 g/mol 589.7 g/mol (mesilate)
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	98%
Protein binding	95%
Metabolism	Hepatic (mainly CYP3A4-mediated)
Half life	18 hours (imatinib) 40 hours (active metabolite)
Excretion	Fecal (68%) and renal (13%)
Therapeutic considerations
Licence data	EU EMEA:link, US FDA:link
Pregnancy cat.	D(AU) D(US)
Legal status	POM(UK) ℞-only(US)
Routes	Oral

Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It was originally coded during development as CGP57148B or STI-571 (these terms are used in early preclinical publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.

It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.

Contents 1 History 2 Uses 3 Tolerability and adverse effects 4 Pharmacology 4.1 Pharmacokinetics 4.2 Mechanism of action 5 Economic aspects 6 See also 7 References 8 External links

History

Imatinib was identified in the late 1990s led by a team of Novartis chemists. Dr. Brian J. Druker of Oregon Health and Science University (OHSU) led many of the key clinical trials confirming the efficacy of imatinib in CML. Its development is the template for rational drug design. Soon after identification of bcr-abl as a drug target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 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.^[1]

Gleevec received FDA approval in May 2001. On the same month it made the cover of TIME magazine as the "magic bullet" to cure cancer.

Uses

Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit.^[2] 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. Early clinical trials also show its potential for treatment of hypereosinophilic syndrome and dermatofibrosarcoma protuberans.

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 with diabetes.^[3]

Recent mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.^[4]

Tolerability and adverse effects

bcr-abl kinase, which causes CML, inhibited by imatinib (small molecule).

In the United States, the Food and Drug Administration has approved imatinib as first-line treatment for CML.^[5] Imatinib has passed through Phase III trials for CML, and has been shown to be more effective than the previous standard treatment of α-interferon and cytarabine. Although the long-term side effects of imatinib have not yet been ascertained, research suggests that it is generally very well tolerated (e.g., liver toxicity was much less than predicted). Broadly, side effects such as edema, nausea, rash and musculoskeletal pain are common but mild.

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.^[6]

Pharmacology

Pharmacokinetics

Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites, only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively.

Mechanism of action

Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously 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 to the ATP binding site of bcr-abl and inhibiting the enzyme activity of the protein competitively.^[7]

Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.^[5] 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.^[8]

Economic aspects

A box of 400-milligram Glivec tablets, as sold in Germany

Gleevec, which costs $32,000 per year for a 400 mg/day dose, is often cited as an example of pharmaceutical industry innovation that justifies the high cost of drugs. Marcia Angell and Arnold S. Relman argue that Gleevec is actually an example of the contribution of taxpayer-supported research and of industry inaction. Dr. Druker tested several, and imatinib was the most potent, and unusually, had almost no effect on normal cells. Novartis had "little corporate enthusiasm," they write, but Druker persisted.^[9]

In 2007, imatinib became a test case through which Novartis challenged India's patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Médecins Sans Frontières argues that a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines.^[10] On 6 August 2007 the Madras High Court, dismissed the writ petition filed by Novartis, challenging the constitutionality of Section 3(d) of Indian Patent Act and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question.

See also

• History of cancer chemotherapy

References

1. ^ Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3-7. PMID 10619854
2. ^ Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. PMID 16779792
3. ^ Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, Cooper ME. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935-42. PMID 14988091
4. ^ Reeves P, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg M, Veach D, Bornmann W, Sherman M, Kalman D (2005). Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med 11 (7): 731-9. PMID 15980865
5. ^ ^{a b} Deininger M, Druker BJ. Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol Rev 2003;55:401-423. PMID 12869662.
6. ^ Risto Kerkelä, Luanda Grazette, Rinat Yacobi, et al.. "Cardiotoxicity of the cancer therapeutic agent imatinib mesylate". Nature Med 12: 908–16. 
7. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
8. ^ Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2001:7:228-234. PMID 11175855
9. ^ [1]How the drug industry distorts medicine and politics: America’s Other Drug Problem, By Arnold S. Relman and Marcia Angell, New Republic, December 16, 2002
10. ^ Médecins Sans Frontières. "As Novartis Challenges India's Patent Law, MSF Warns Access to Medicines Is Under Threat", 2006-09-26. Accessed 2006-02-10.

External links

• NCI Drug Information Summary for Patients

v • d • e Targeted therapy / extracellular chemotherapeutic agents/antineoplastic agents (L01) CI monoclonal antibodies ("-mab") Receptor tyrosine kinase ErbB: HER1/EGFR (Cetuximab, Panitumumab) · HER2/neu (Trastuzumab) Others for solid tumors EpCAM (Catumaxomab, Edrecolomab) · VEGF-A (Bevacizumab) Leukemia/lymphoma lymphoid: CD20 (Rituximab, Tositumomab, Ibritumomab) myeloid: CD52 (Alemtuzumab) L+M: CD33 (Gemtuzumab) Tyrosine kinase inhibitors ("-nib") Receptor tyrosine kinase ErbB: HER1/EGFR (Erlotinib, Gefitinib, Lapatinib, Vandetanib, Neratinib) · HER2/neu (Lapatinib, Neratinib) RTK class III: C-kit (Axitinib, Sunitinib, Sorafenib, Toceranib) · FLT3 (Lestaurtinib) · PDGFR (Axitinib, Sunitinib, Sorafenib, Toceranib) VEGFR (Vandetanib, Semaxanib, Cediranib, Axitinib, Sunitinib, Sorafenib, Toceranib) Non-receptor bcr-abl (Imatinib, Nilotinib, Dasatinib) Src (Bosutinib) Janus kinase 2 (Lestaurtinib) Other fusion protein against VEGF (Aflibercept) · exotoxin against IL-2 (Denileukin diftitox)

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