Brands, Medical Use, Clinical Data
- Antineoplastic Agents
- Protein Kinase Inhibitors
Brands / Synonyms
Gleevec; Glivec; Imatinib Mesylate; Imatinib Methansulfonate
For the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML). Also indicated for the treatment of pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy. Also indicated with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).
Imatinib is an antineoplastic agent used to treat chronic myelogenous leukemia. Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. 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.
Mechanism of Action
Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib also inhibits the receptor tyrosine kinases for platelet derived growth factor (PDGF) and stem cell factor (SCF) - called c-kit. Imatinib was identified in the late 1990s by Dr Brian J. Druker. Its development is an excellent example of rational drug design. Soon after identification of the bcr-abl 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.
Imatinib is well absorbed with mean absolute bioavailability is 98% with maximum levels achieved within 2-4 hours of dosing
Side effects include nausea, vomiting, diarrhea, loss of appetite, dry skin, hair loss, swelling (especially in the legs or around the eyes) and muscle cramps
Biotrnasformation / Drug Metabolism
Primarily hepatic via CYP3A4. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4.
Use of Gleevec® (imatinib mesylate) is contraindicated in patients with hypersensitivity to imatinib or to any
other component of Gleevec.
Drugs that may alter imatinib plasma concentrations
Drugs that may increase imatinib plasma concentrations:
Caution is recommended when administering Gleevec with inhibitors of the CYP3A4 family (e.g., ketoconazole,
itraconazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity
may decrease metabolism and increase imatinib concentrations. There is a significant increase in exposure to imatinib
when Gleevec is coadministered with ketoconazole (CYP3A4 inhibitor).
Drugs that may decrease imatinib plasma concentrations:
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations.
Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital or St.
John's Wort) may significantly reduce exposure to Gleevec. Pretreatment of healthy volunteers with multiple doses of
rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly
(p<0.05) decreased mean cmax and AUC(0-8). In patients where rifampin or other CYP3A4 inducers are
indicated, alternative therapeutic agents with less enzyme induction potential should be considered.
Drugs that may have their plasma concentration altered by Gleevec
Gleevec increases the mean cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold,
respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering
Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine or pimozide). Gleevec will
increase plasmaconcentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine
calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).
Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive
low-molecular weight or standard heparin.
in vitro, Gleevec inhibits the cytochrome P450 isoenzyme CYP2D6 activity at similar concentrations that
affect CYP3A4 activity. Systemic exposure to substrates of CYP2D6 is expected to be increased when coadministered
with Gleevec. No specific studies have been performed and caution is recommended.
in vitro, Gleevec inhibits acetaminophen O-glucuronidation (Ki value of 58.5 µM) at therapeutic
levels. Systemic exposure to acetaminophen is expected to be increased when coadministered with Gleevec. No specific
studies in humans have been performed and caution is recommended.