Gleevec - General Information
Gleevec 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 is occasionally referred to as CGP57148B or STI571 (especially in older 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.
Pharmacology of Gleevec
Gleevec is an antineoplastic agent used to treat chronic myelogenous leukemia. Gleevec 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, Gleevec is used to decrease Bcr-Abl activity.
Gleevec for patients
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.
Use of Gleevec® (imatinib mesylate) is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec.
Additional information about Gleevec
Gleevec Indication: 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).
Mechanism Of Action: Gleevec 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. Gleevec also inhibits the receptor tyrosine kinases for platelet derived growth factor (PDGF) and stem cell factor (SCF) - called c-kit. Gleevec 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.
Drug Interactions: Acetaminophen Increased hepatic toxicity of both agents
Anisindione Gleevec increases the anticoagulant effect
Dicumarol Gleevec increases the anticoagulant effect
Acenocoumarol Gleevec increases the anticoagulant effect
Warfarin Gleevec increases the anticoagulant effect
Aprepitant Aprepitant may change levels of chemotherapy agent
Atorvastatin Increases the effect and toxicity of atorvastatin
Carbamazepine Carbamazepine decreases levels of imatinib
Cerivastatin Gleevec increases the effect and toxicity of statin
Cyclosporine Gleevec increases the effect and toxicity of cyclosporine
Dexamethasone Dexamethasone decreases levels of imatinib
Lovastatin Gleevec increases the effect and toxicity of statin
Simvastatin Gleevec increases the effect and toxicity of statin
St. John's Wort St. John's Wort decreases levels of imatinib
Rifampin Rifampin decreases levels of imatinib
Pimozide Increases the effect and toxicity of pimozide
Phenobarbital Phenobarbital decreases levels of imatinib
Nifedipine Gleevec increases the effect and toxicity of nifedipine
Clarithromycin The macrolide increases levels of imatinib
Erythromycin The macrolide increases levels of imatinib
Josamycin The macrolide increases levels of imatinib
Ketoconazole The imidazole increases the levels of imatinib
Itraconazole The imidazole increases the levels of imatinib
Ethotoin The hydantoin decreases the levels of imatinib
Fosphenytoin The hydantoin decreases the levels of imatinib
Mephenytoin The hydantoin decreases the levels of imatinib
Phenytoin The hydantoin decreases the levels of imatinib
Food Interactions: Take with food to reduce the incidence of gastric irritation. Follow with a large glass of water. A lipid rich meal will slightly reduce and delay absorption. Avoid grapefruit and grapefruit juice throughout treatment, grapefruit can significantly increase serum levels of this product.
Generic Name: Imatinib
Synonyms: Imatinib Mesylate; Imatinib Methansulfonate
Drug Category: Antineoplastic Agents; Protein Kinase Inhibitors
Drug Type: Small Molecule; Approved
Absorption: Imatinib is well absorbed with mean absolute bioavailability is 98% with maximum levels achieved within 2-4 hours of dosing
Toxicity (Overdose): 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
Protein Binding: Very high (95%)
Biotransformation: 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.
Half Life: 18 hours for Imatinib, 40 hours for its major active metabolite, the N-desmethyl derivative
Dosage Forms of Gleevec: Tablet Oral
Chemical IUPAC Name: 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
Chemical Formula: C29H31N7O
Imatinib on Wikipedia: https://en.wikipedia.org/wiki/Imatinib
Organisms Affected: Humans and other mammals