Imatinib Mesylate

Imatinib mesylate (gleevec, glivec; 4-[(4-methyl-1-piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl]benzamidemethanesulfonate) was developed through combined use of high throughput screening and medicinal chemistry. Imatinib inhibits protein tyrosine kinase activities of ABL and its activated derivatives v-ABL, BCR-ABL, and EVT6-ABL, the platelet-derived growth factor receptor (PDGFR), and KIT receptor tyrosine kinases. Imatinib binds in the ATP-binding site of the kinase domain and exhibits a high level of selectivity towards these three kinases. Complete inhibition of proliferation with cell death through apoptosis occurs in cells dependent on activated ABL, KIT, or PDGFR for proliferation. This includes cells expressing BCR-ABL in CML, mutant KIT isoforms associated with gastrointestinal stromal tumors (GISTs), the ETV6-PDGFR fusion associated with a subset of chronic myelomonocytic leukemia (CMML), and the FIP1L1-PDGFRA fusion associated with hypereosinophilic syndrome (HES).

Resistance to imatinib can be manifested by a failure to achieve a specific desired response (i.e., primary) or by the loss of a desired response (i.e., secondary). Secondary resistance predominantly results from mutations in the kinase domain that render it less sensitive to imatinib, although some patients have amplification of the kinase target.

Imatinib is nearly completely absorbed after oral administration with peak plasma concentrations achieved within 2-4 hours. Following oral administration in healthy volunteers, the elimination t1/2 of imatinib and its major active metabolite, the N-desmethyl derivative, are ~18 and 40 hours, respectively. There is no significant change in the pharmacokinetics of imatinib on repeated dosing or with administration of food. Doses >300 mg/day achieve trough levels of 1 mM, which corresponds to in vitro levels required to kill BCR-ABL—expressing cells. Improved responses may be observed with doses of 600 or 800 mg/day compared to 400 mg/day, consistent with dose-dependent inhibition of the kinase.

CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other CYPs play a minor role in imatinib's metabolism. Imatinib increased the peak plasma concentration and AUC of simvastatin by 2 and 3.5 times, respectively, and coadministration with rifampin, an inducer of CYP3A4, reduces plasma imatinib AUC by ~70%. Elimination of imatinib occurs predominantly in the feces, mostly as metabolites.

Imatinib has efficacy in diseases in which the ABL, KIT, or PDGFR have dominant roles in driving the proliferation of the tumor because of mutations that result in constitutive activation of the kinase, either by fusion with another protein or point mutations. Thus, imatinib shows remarkable therapeutic benefits in patients with CML (BCR-ABL), GIST (KIT mutation positive), CMML (EVT6-PDGFR), HES (FIP1L1-PDGFR), and dermatofibrosarcoma protuberans (constitutive production of the ligand for PDGFR). The situation in GIST is particularly instructive, as patients with an exon 11 mutation of KIT have a significantly higher partial response rate (72%) than those with no detectable KIT mutations (9%). Thus, KIT mutational status predicts response. The currently recommended dose of imatinib is 400-600 mg/day.

The most frequently reported drug-related adverse events are nausea, vomiting, edema, and muscle cramps. Most events are mild to moderate, and only 2-5% of patients permanently discontinue therapy, most commonly because of rashes and elevations of transaminases (each in <1% of patients). Edema can manifest at any site, most commonly in the ankles and periorbital tissues. Severe fluid retention (pleural effusion, pericardial effusion, pulmonary edema, and ascites) is reported in 1-2% of patients taking imatinib. The probability of edema increases with higher imatinib doses and in persons >65 years old. Neutropenia and thrombocytopenia are consistent findings in all studies in leukemia patients, with a higher frequency at doses >750 mg. The occurrence of cytopenias also is dependent on the stage of CML, with a frequency of severe neu-tropenia and thrombocytopenia between two- and threefold higher in blast crisis and accelerated phase compared to chronic phase. In solid tumor patients, severe neutropenia has been reported in <5% of patients. Thrombocytopenia is much less common.

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