indication

For the treatment Philadelphia chromosome positive chronic myeloid leukemia (CML) and malignant gastrointestinal stromal tumors (GIST).

pharmacology

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.

toxicity

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

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.

absorption

Imatinib is well absorbed with mean absolute bioavailability is 98% with maximum levels achieved within 2-4 hours of dosing

half life

18 hours for Imatinib, 40 hours for its major active metabolite, the N-desmethyl derivative

route of elimination

Imatinib elimination is predominately in the feces, mostly as metabolites.

drug interactions

Acenocoumarol: Imatinib may increase the anticoagulant effect of acenocoumarol.

Acetaminophen: Increased hepatic toxicity of both agents

Anisindione: Imatinib may increase the anticoagulant effect of anisindione.

Aprepitant: Aprepitant may change levels of the chemotherapy agent, imatinib.

Atorvastatin: Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if imatinib is initiated, discontinued or dose changed.

Bromazepam: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if imatinib is initiated, discontinued or dose changed. Dosage adjustments may be required.

Carbamazepine: Carbamazepine, a strong CYP3A4 inducer, may increase the metabolism of imatinib. Imatinib, a strong CYP3A4 inhibitor, may increase the metabolism of carbamazepine. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or dose changed.

Cerivastatin: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of cerivastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if imatinib is initiated, discontinued or dose changed.

Clarithromycin: The macrolide, clarithromycin, may increase the serum concentration of imatinib.

Cyclosporine: Imatinib increases the effect and toxicity of cyclosporine

Dantrolene: Imatinib may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if imatinib is initiated, discontinued or dose changed.

Dexamethasone: Dexamethasone may decrease levels of imatinib.

Dicumarol: Imatinib may increase the anticoagulant effect of dicumarol.

Erythromycin: The macrolide, erythromycin, may increase the serum concentration of imatinib.

Ethotoin: The hydantoin decreases the levels of imatinib

Fosphenytoin: The hydantoin decreases the levels of imatinib

Itraconazole: Itraconazole may increase the levels of imatinib.

Josamycin: The macrolide, josamycin, may increase the serum concentration of imatinib.

Ketoconazole: Ketoconazole may increase the levels of imatinib.

Lovastatin: Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of lovastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if imatinib is initiated, discontinued or dose changed.

Mephenytoin: The hydantoin decreases the levels of imatinib

Nifedipine: Imatinib increases the effect and toxicity of nifedipine

Phenobarbital: Phenobarbital decreases levels of imatinib

Phenytoin: The hydantoin decreases the levels of imatinib

Pimozide: Imatinib may increase the effect and toxicity of pimozide.

Rifampin: Rifampin decreases levels of imatinib

Simvastatin: Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if imatinib is initiated, discontinued or dose changed.

St. John's Wort: St. John's Wort decreases levels of imatinib

Tacrolimus: The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Imatinib is initiated, discontinued or dose changed.

Tadalafil: Imatinib may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Imatinib may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Imatinib may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Imatinib is initiated, discontinued or dose changed.

Tamsulosin: Imatinib, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Imatinib is initiated, discontinued, or dose changed.

Telithromycin: Co-administration may result in altered plasma concentrations of Imatinib and/or Telithromycin. Consider alternate therapy or monitor the therapeutic/adverse effects of both agents.

Temsirolimus: Imatinib may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Imatinib is initiated, discontinued or dose changed.

Tiagabine: The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Imatinib is initiated, discontinued or dose changed.

Tolterodine: Imatinib may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The BCRP/ABCG2 inhibitor, Imatinib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Imatinib is initiated, discontinued or dose changed.

Tramadol: Imatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Imatinib may decrease the effect of Tramadol by decreasing active metabolite production.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Trazodone: The CYP3A4 inhibitor, Imatinib, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Imatinib is initiated, discontinued or dose changed.

Trimipramine: The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Imatinib is initiated, discontinued or dose changed.

Vardenafil: Imatinib, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.

Venlafaxine: Imatinib, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Imatinib is initiated, discontinued, or dose changed.

Verapamil: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Imatinib is initiated, discontinued or dose changed.

Vinblastine: Imatinib, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Imatinib is initiated, discontinued or dose changed.

Vincristine: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Imatinib is initiated, discontinued or dose changed.

Vinorelbine: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Imatinib is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of imatinib by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of imatinib if voriconazole is initiated, discontinued or dose changed.

Warfarin: Imatinib may increase the anticoagulant effect of warfarin increasing the risk of bleeding. Monitor for changes in prothrombin time and therapeutic and adverse effects of warfarin if imatinib is initiated, discontinued or dose changed.

Zonisamide: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if imatinib is initiated, discontinued or dose changed.

Zopiclone: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if imatinib is initiated, discontinued or dose changed.