Gleevec, Glivec Review Article
Imatinib, marketed by Novartis as Gleevec (U.S.) or Glivec (Europe/Australia/Latin America), is a competitive tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). Like all tyrosine-kinase inhibitors, imatinib works by preventing a central tyrosine kinase enzyme, in this case BCR-Abl, from phosphorylating subsequent proteins and initiating the signaling cascade necessary for cancer development, thus preventing the growth of cancer cells and leading to their death by apoptosis. Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug's action.In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.
Gleevec, Glivec generic (generic - what is it?)
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By 2011, Gleevec has been FDA approved to treat ten different cancers. NATCO an Indian drug company also makes a generic version of Gleevec called Veenat. In India generic Gleevec is available also available under the name of "Imatib". It is manufacturing & marketing by CIPLA drug company.
Gleevec (imatinib) is a protein-tyrosine kinase inhibitor, which is used orally for treatment of a certain type of blood cancer, namely Philadelphia chromosome-positive chronic myelogenous leukaemia (CML), as well as for the treatment of gastrointestinal stromal tumours (GIST). It was approved by FDA in 2001.
Gleevec inhibits tyrosine kinase, which leads to a reduction in the growth of cancer cellsImatinib is marketed as its mesylate salt, imatinib mesilate.
Long-Term Response to imatinib in Newly Diagnosed CML
Cumulative best response At 12 months At 60 months
Complete haematologic response 96% 98%
Major cytogenetic response 85% 92%
Complete cytogenetic response 69% 87%
Before the discovery of Gleevec, there were only two treatments available for CML. The first option was bone marrow transplantation, which was not possible for many patients as it is a very risky procedure and not more than 25% of the patients were able to undergo it due to age and other restrictive factors. The second option was constant interferon infusion, which also had many side effects. Statistical data shows that only 30% of patients survived even five years after being diagnosed with CML. (Druker, et al, 1996, 2001, 2006 and Pray, 2008)
Gleevec is sometimes referred to as a “miracle drug”. Oncologist Brian Drucker and his colleagues have been conducting clinical trials and studies on this drug from the very beginning of its synthesis. In 2001, they reported that 53 out of 54 patients responded to a four-week treatment of imatinib with a dose of 300 mg a day, and their white blood cells returned to a normal level. In 2006, a five-year follow-up study report was published and it was seen that after completion of a 60-month imatinib therapy, 98% patients have shown complete response with a survival rate of 89% and a recurrence rate of 17%. (Druker, et al, 1996, 2001, 2006 and Pray, 2008)
Chronic Myelogenous Leukaemia Statistics:
Though the average age for developing CML is 65, one in every 625 people is at lifetime risk for developing the disease. In 2011, the American Cancer Society estimated 5,150 persons to be affected with CML only in USA. CML comprises of 15%-20% of all occurrences of adult leukaemia in the Western population. (Howlader, 1975-2008)
Mechanisms of Action:
Gleevec is a 98% bioavailable drug, which means 98% of imatinib taken orally reaches the blood stream. It is metabolized in the liver to a great extent by the enzyme CYP3A4, as well as CYP1A2, CYP2D6, CYP2C9, and CYP2C19.
Sometimes an abnormal chromosome forms in human body cells called the Philadelphia chromosome. These Philadelphia chromosomes code for an abnormal protein named BCR-ABL. BCR-ABL speeds up cell division causing genetic abnormalities and increasing the number of abnormal cancerous cells in the body, ultimately causing CML. This BCR-ABL protein has a tyrosine kinase domain in it. The function of tyrosine kinase is to transfer a phosphate from ATP to the protein cellImatinib is highly specific for the tyrosine kinase domain of BCR-ABL. It binds with the TK domain of BCR-ABL, prohibiting the enzyme activity of the protein, therefore, inhibiting proliferation of tumours or cancer cells. (Sokal, et al., 1998, Gambacorti-Passerini, et al., 2003)
Imatinib is available on the market in tablet forms of 100 mg and 400 mg. The dose varies in children from 260/m2 per day to 340/m2 per day, but should never exceed 600 mg a day. In adults, it varies from 400 mg to 800 mg per day, as per the physician’s prescription (Wilkes and Burke, 2011).
1. It was initially synthesised for the treatment of Philadelphia chromosome-positive chronic myelogenous leukaemia. It is the first generation of tyrosine kinase inhibitor drugs. Before Imatinib, no drugs could change the natural progression of the disease. It is effective in 65%-75% of patients with chronic myelogenous leukaemia.
2. Gastrointestinal stromal tumours were non-responsive to chemotherapy, but the use of imatinib has shown marked efficacy (up to 80%) in survival of patients with an advanced form of the disease, and lowered the chances of further recurrence to 6% with adjuvant treatment for up to three years.
3. Because of the tyrosine kinase blocking properties, it has shown effectiveness in treating specific types of plexiform neurofibromas.
4. Studies and clinical trials have shown that imatinib can also effectively treat pulmonary hypertension, pulmonary fibrosis, and Alzheimer’s disease. (Millot, et al., 2011)
The following side effects can be seen after long-term or short-term use of imatinib:
1. Taste changes, loss of appetite, stomach ache, nausea, vomiting, bloating, diarrhoea, bloody stool, tarry stool, and constipation.
2. Weakness, dizziness, anxiety, depression, confusion, and trouble sleeping.
3. Cough, fever, chills, sore throat, night sweat, stuffy nose, runny nose, shortness of breath, chest tightness, chest pain, and irregular heart beat.
4. Headache, joint pain, muscle pain, and bone pain.
5. Hair loss, increased tearing, change in amount of urine production, change in colour of urine, unusual and sudden weight gain or weight loss, and swelling of hand, feet, or face.
6. Vision problem, slurred speech, and problem swallowing.
7. Skin irritation, skin rashes, blistering or peeling of skin, increased bruising, skin and eye yellowing.
Ingestion of substances like grape juice or St. John’s wort should be avoided during the administration of imatinib, as these substances have been shown to change the plasma concentration of the drug. If imatinib is being administrated to children, their growth rate can be significantly reduced. Growth rate in children should be constantly monitored and proper measurement should be taken to avoid this.
Gleevec has a total of 698 drug interactions within which 41 drugs show major interaction. As imatinib is metabolized by CYP3A4, every other drug which affects the activity of CYP3A4 can also change the concentration of imatinib in the blood plasma, causing side effects. Some of the 41 drugs known to cause major interaction with Imatinib, are mentioned below:
1. Antifungal and antibiotics like ketoconazole, itraconazole, and clarithromycin, block CYP3A4 and increase the level of imatinib in the blood, causing side effects.
2. Bactericidals like rifampin and rifabutin increase the activity of CYP3A4, decreasing the efficacy and level of imatinib in the blood stream.
3. Other substrates of CYP3A4 like metoprolol, paracetamol, warfarin, and immunosuppressanta, are contraindicated to be administered along with imatinib, as the plasma concentration of these drugs can increase due to inhibition of CYP3A4 by imatinib, hence causing severe side effects.
Gleevec is a first generation tyrosine kinase inhibitor, which has high degree of efficacy seen in patients with Philadelphia chromosome-positive chronic myelogenous leukaemia. In a few cases, imatinib resistance has been seen, but despite that concern, successful clinical trials and studies have continued.
Druker, BJ, et al, 1996, Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells, Nature Medicine;2:561–566.
Druker, BJ, et al, 2001, Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukaemia, New England Journal of Medicine;344:1031–1037.
Druker, BJ, et al, 2006, Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia, New England Journal of Medicine;355:2408–2417.
Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L., 2003, "Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias", Lancet Oncol.;4(2):75–85.
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Millot F, Baruchel A, Guilhot J, Petit A, Leblanc T, Bertrand Y, Mazingue F, Lutz P, V?rit? C, Berthou C, Galambrun C, Bernard F, Yacouben K, Bordigoni P, Edan C, Reguerre Y, Couillault G, M?chinaud F, Cayuela JM, Guilhot F., 2011, imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial, 2011, J Clin Oncol.;29(20):2827-32.
Pray, L, 2008, Gleevec: the breakthrough in cancer treatment, Nature Education;1(1).
Sokal J, Baccarani M, Russo D, Tura S, 1988, "Staging and prognosis in chronic myelogenous leukemia", Semin Hematol;25(1):49–61.
Wilkes, GM, Barton-Burke, M, 2011, Oncology Nursing Drug Handbook, Jones & Bartlett Publishers.
Gleevec, Glivec Review Article