Imatinib

Imatinib is a prescription drug used for the treatment of some leukemias and other cancers. Cancers are characterized by uncontrolled growth of cells, and leukemia is a specific type of cancer characterized by uncontrolled proliferation of white blood cells. Imatinib represents a milestone in cancer therapy as the the first tyrosine kinase inhibitor to become a marketed drug. Tyrosine kinases are a class of enzymes that promote the growth and replication of cells. Inhibitors like imatinib bind to the receptor that activates tyrosine kinase and reduces its activity. The Food and Drug Administration approved the use of imatinib in May 2001. At the same time, the U.S. magazine Time heralded the drug as a "magic bullet" against cancer.

Other Names

When formulated as the mesylate salt, imatinib is marketed by Novartis in the North America as Gleevec and in Europe as Glivec.

Uses

Imatinib is used to treat many different types of cancer. It is used in Philadelphia chromosome positive (PH+) myeloid leukemias. These leukemias are characterized by two genes, which are located on different chromosomes, switching places with each other (see video above). Myeloid leukemias are associated with uncontrolled proliferation of immature white blood cells that flood the bloodstream. Imatinib is used for Philadelphia chromosome positive myeloid leukemias under the following conditions:

• New diagnosis adult patients with Ph+ chronic myeloid leukemia (PH+ CML) in the chronic phase
• Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of [[interferon-alpha] therapy
• children with a new diagnosis of PHI + CML in chronic phase, or whose disease has recurred after stem cell transplant, or who are resistant to interferon-therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia (Ph+ ALL)

Imatinib is also used for the following cancers:

• Those characterized by uncontrolled growth of blood cells (myelodysplastic/ myeloproliferative diseases (MDS/MPD)) in adults
• Aggressive infiltration of mast cells into tissues (mastocytosis (ASM)) in adults
• Proliferation of eosinophil cells (hypereosinophilic syndrome) and/or chronic eosinophilic leukemia (HES/CEL) in adults
• Unresectable, recurrent and/or spreading (metastatic) dermatofibrosarcoma protuberans (DFSP) in adults
• Unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST)

How Imatinib is Taken

Imatinib is available in 100-mg and 400-mg tablets. The dosage depends on the cancer being treated.

Adults with Ph+ CML CP, AP and blast crisis

The recommended dose of imatinib is 400 mg/day for adults in chronic phase CML and 600 mg/day for adults in accelerated phase or blast crisis.

Children with Ph+ CML

The recommended dose of imatinib for children with newly diagnosed Ph+ CML is 340 mg/m²/day (m² is square meter of body surface area). The dose is not to exceed 600 mg. The recommended dose is 260 mg/m²/day for children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon-alpha therapy.

Ph+ ALL

The recommended dose of imatinib is 600 mg/day for adults with relapsed/refractory Ph+ ALL.

MDS/MPD or ASM

The recommended dose of imatinib is 400 mg/day for adults with MDS/MPD or ASM. Treatment is sometimes reduced to 400 mg/day for ASM if other therapies have failed. Some patients start on 100 mg/day and slowly increase the dose to 400 mg/day if the treatment is ineffective and not associated with intolerable side effects.

HES/CEL

For HES/CEL, the recommended dose of imatinib is 400 mg/day. Some patients may be eligible for treatment with 100 mg/day with a gradual increase to 400 mg/day if treatment is well-tolerated but ineffective.

DFSP

For DFSP, the recommended dose of imatinib is 800 mg/day.

GIST

The recommended dose of imatinib is 400 mg/day or 600 mg/day for adults with unresectable and/or metastatic, malignant GIST.

How Imatinib Works

Imatinib is a tyrosine kinase inhibitor. Tyrosine kinases, when mutated and/or abnormally activated, are enzymes that have been implicated in the development of some cancers. Tyrosine kinases catalyze the addition of a phosphorus group to tyrosine residues in proteins; in many cases, the phosphotyrosine-containing protein becomes active in transducing a growth signal to other parts of the cell.

Imatinib inhibits the tyrosine kinase called bcr-abl. This kinase is activated by proteins encoded by the genes that switch places in Ph+ CML. Imatinib also inhibits tyrosine kinases that are activated by other proteins.

How the Body Affects Imatinib

Imatinib is well absorbed by the body, and peak levels in the blood are reached approximately 2–4 hours after dosing. Imatinib is metabolized in the liver, primarily by an enzyme called CYP3A4. The time needed for the concentration of the drug in the blood to be reduced by half, the half-life, is approximately 18 hours. However, the compound created by CYP3A4-mediated metabolism is also active. This compound has a half-life of approximately 40 hours. Most of imatinib is eliminated from the body in the feces.

Side Effects

The most common side effects of imatinib reported in clinical trials were the following:

• edema (fluid accumulation), most often around the eyes or in the legs
• nausea and vomiting
• muscle cramps
• musculoskeletal pain
• diarrhea
• rash

Risks and Precautions

Imatinib can adversely affect the blood, liver, and heart. It can reduce the number of white blood cells and platelets in the blood. Some patients have elevated markers of liver damage in the blood during treatment. Blood tests can be taken to detect blood and liver changes and reduce the risk of any complications of treatment. Congestive heart failure has been reported in a small number of people receiving imatinib.

Animal tests have shown that imatinib harms the fetus. No studies on the effects of imatinib on pregnancy have been conducted in humans. Whether imatinib crosses into breast milk is not known.

Drug Interactions

Because imatinib is metabolized by several liver enzymes, it has the potential to interact with numerous drugs.

CYP3A4 inducers

Some drugs increase the activity of CYP3A4. These drugs are called CYP3A4 inducers. Some CYP3A4 inducers include rifampin (Rifadin, Rimactane) and carbamazepine (Tegretol). These drugs could increase the metabolism of imatinib, and sometimes the dose of imatinib may need to be adjusted to compensate.

CYP3A4 inhibitors

Drugs that inhibit CYP3A4 activity may decrease imatinib metabolism, increase blood concentrations, and increase the risk of side effects. Strong CYP3A4 inhibitors include the following:

• antifungals (e.g., ketoconazole (Nizoral), itraconazole (Sporanox), and voriconazole (Vfend))
• antibiotics (e.g., erythromycin, clarithromycin (Biaxin), telithromycin (Ketek))
• antiretrovirals (e.g., nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Fortovase))
• nefazodone (Serzone)
• Some components of grapefruit and grapefruit juice

Other drugs metabolized by CYP3A4

Drugs used in combination and metabolized by the same enzyme have the potential to interact. This is because they compete for sites on the enzyme. The interaction can result in elevated concentrations of one or both of the drugs. Some drugs that are primarily metabolized by CYP3A4 are listed below:

• Immunosuppressants (e.g., cyclosporine (Neoral), tacrolimus (Rapimmune))
• Pain relievers (e.g., alfentanil (Alfenta), fentanyl (Duragesic))
• Ergot derivatives (e.g., diergotamine, ergotamine)
• Pimozide (Orap)
• Quinidine
• Sedatives (e.g., alprazolam (Xanax))
• Calcium channel blockers (e.g., nifedipine (Adalat))
• Statins (e.g., atorvastatin (Lipitor))

The anticoagulant warfarin is also partly metabolized by CYP3A4. To eliminate the risk of an interaction, heparin is used with imatinib in people who require blood thinning.

Drugs metabolized by CYP2D6

Imatinib inhibits CYP2D6, which is another drug-metabolizing enzyme in the liver. Thus, imatinib could increase the concentrations of drugs that are metabolized by CYP2D6. Many antidepressants and antipsychotics are metabolized by CYP2D6.

Other drugs

Although not documented, levels of acetaminophen (Tylenol) are expected to increase if given with imatinib.

History

Imatinib is the result of a long series of discoveries and focused research efforts into how normal cells become malignant. ^[1][2] As with many drugs currently on the market, initial efforts were helped by the discovery of biologically active compounds present in natural products. The structure of several naturally-occurring tyrosine kinase inhibitors revealed similarities that proved to be important in designing subsequent drug candidates.

Controversy

Generic formulations of drugs are allowed to be marketed once the initial drug patents expire, often resulting in sharply decreased profits for the original (brand-name) product.^[3] In India, patents expire more quickly than they do in many other countries. One major advantage of these short patents is that much-needed drugs become available at a lower cost. Novartis challenged India’s patent laws in 2007 in order to delay the anticipated flood of generic imatinib. In August of the same year, the Novartis claim was dismissed by the High Court of Chennai as unconstitutional.

Research

An analysis of over 1,800 patients showed that about half treated with imatinib had at least a 50% reduction of advanced GIST.^[4]

A review of trials and other studies found that imatinib and conventional treatments produced similar one-year survival rates in patients with chronic phase CML. ^[5] However, imatinib treatment was associated with greater rates of remission and was more effective in patients in accelerated phase CNML.

References

1. ↑ Gambacorti-Passerini C. Part I: Milestones in personalised medicine--imatinib. Lancet Oncol. 2008 Jun;9(6):600.
2. ↑ Hunter T. Treatment for chronic myelogenous leukemia: the long road to imatinib. J Clin Invest. 2007 Aug;117(8):2036-43. Abstract | Full Text | PDF
3. ↑ Dalen DM, Strøm S, Haabeth T. Price regulation and generic competition in the pharmaceutical market. Eur J Health Econ. 2006 Sep;7(3):208-14. Abstract
4. ↑ Wilson J, Connock M, Song F, et al. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation. Health Technol Assess. 2005 Jul;9(25):1-142. Abstract | Full Text
5. ↑ Garside R, Round A, Dalziel K, Stein K, Royle P. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review. Health Technol Assess. 2002;6(33):1-162. Summary | PDF

External Links

National Cancer Institute

FDA: Patient Information Sheet