Tyrosine Kinase Inhibitors

The analysis of the human genome has revealed 518 putative protein kinase genes.2 3 Of these genes, a subset of approximately 90 are responsible for protein tyrosine kinases.2 3 Various protein tyrosine kinases have been implicated in the pathophysiology of malignant conditions. Increased activity or deregulation of these kinases results in alterations in normal downstream cellular signaling. Examples of such processes include the bcr-abl fusion protein in chronic myeloid leukemia and HER-2 overexpression in breast cancer.

Recently, numerous targeting methodologies have been employed to inhibit specific tyrosine kinases in various malignancies. The most promising binding site for such inhibitors has been the adenosine triphosphate (ATP) complex binding site. Although a consistent structure within various tyrosine kinases, minor nuances in this catalytic domain configuration has allowed the development of highly selective inhibitors.4


Historically, chronic myelogenous leukemia (CML) was treated with agents that had little effect on overall survival (hydroxyurea and busulfan) or induced such toxicity that effective doses were rarely maintained (interferon). Imatinib, a phenylaminopyrimi-dine derivative, is a selective tyrosine kinase inhibitor used in the treatment of Philadelphia chromosome positive leukemia. This orally administered agent represented a breakthrough in the therapy of CML, and more recently has been integrated into Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) treatment regimens.

Imatinib's ability to competitively inhibit the ATP binding site of the bcr-abl tyrosine kinase prevents phosphorylation of proteins involved in signal trans-duction.5 By inhibiting the aberrant tyrosine kinase, imatinib halts cellular proliferation and tumor formation by bcr-abl expressing cells and decreases CML

colony growth without inhibiting normal colony growth.67 This inhibition is accomplished not only by the parent compound, but also by the active N-demethylated piperazine metabolite.

In addition to the pharmacological activity described above, the drug has exhibited the ability to inhibit the tyrosine kinase activity of c-kit, platelet-derived growth factor (PDGF), and stem cell factor (SCF). The former has led to its utility in gastrointestinal stromal tumor therapy.8 Imatinib also inhibits tyrosine kinase activity of abl in normal cells, although this is not considered clinically relevant.5

While a large number of patients have experienced clinical benefit from receiving imatinib, success has not been uniform. Some patients have exhibited de novo resistance, while others have developed resistant disease after an initial favorable response. This resistance may be multifactorial, with possible variables including gene and protein amplification, mutations in the protein kinase, binding of imatinib to proteins in the plasma, and additional oncogenic mutations that may bestow an additional growth advantage on the cells.9-11


Oral imatinib is well absorbed, with a bioavailability of nearly 100%.12 Peak plasma concentration occurs within 4 h of administration, regardless of whether or not the dose is taken with food.13 Following oral administration, the elimination half-lives of imatinib and its major active metabolite are approximately 18 and 40 h, respectively.13 Repeat dosing does not have a significant impact on the drug's pharmacokinetics and accumulation is 1.5 to 2.5fold with daily administration.1213 In-vitro models have established that at clinically relevant concentrations, imatinib is approximately 95% protein bound, primarily to albumin and a1-acid glycoprotein.12 Hepatic enzymes, predominantly the cytochrome P450-3A4 isoenzyme, are responsible for the drug's metabolism.13 Other cytochrome enzymes, such as CYP1A2, CYP2D6, CYP 2C9, and CYP 2C19, also contribute to imatinib's degradation.13 Because many other medications can affect this metabolic system, imatinib is susceptible to alterations in kinetics/dynamics via cytochrome-based drug-drug interactions (Table 102.1) Most of the oral dose is eliminated via the feces and only 5% is excreted unchanged through the urine.13

Table 102.1 Imatinib CYP450 mediated drug-drug interactions13

Interacting medication Result

Alfuzosin Imatinib's enzyme inhibition results in increased alfuzosin exposure

Aprepitant Enzyme inhibition by aprepitant may result in elevated plasma concentrations of imatinib

Carbamazepine Significant decrease in exposure to imatinib may occur when coadministered with the enzyme inducer carbamazepine

Clarithromycin Clarithromycin may decrease the metabolism and increase concentrations of imatinib

Cyclosporine Plasma concentrations of cyclosporine may be altered when coadministered with imatinib

Dexamethasone Significant decrease in exposure to imatinib may occur when coadministered with dexamethasone

Eletriptan Increased exposure to eletriptan may be expected when eletriptan is used concomitantly with imatinib

Erythromycin Erythromycin may decrease the metabolism and increase concentrations of imatinib

Itraconazole, ketoconazole, Azole antifungals may decrease the metabolism and increase concentrations of imatinib voriconazole

Phenobarbital Significant decrease in exposure to imatinib may occur when coadministered with the enzyme inducer phenobarbital

Phenytoin Significant decrease in exposure to imatinib may occur when coadministered with the enzyme inducer phenytoin

Rifabutin, rifampin Imatinib is susceptible to significantly increased clearance when coadministered with enzyme inducers such as rifampin and rifabutin

Simvastatin Plasma concentrations of simvastatin may be increased when coadministered with imatinib

St. John's Wort Concomitant use of imatinib and St. John's Wort resulted in significantly increased clearance of imatinib

Warfarin Concurrent treatment with imatinib and warfarin may increase the bioavailability of warfarin, sthereby increasing the risk of bleeding


The majority of patients who received imatinib in clinical studies did experience side effects, but most of these effects were mild or moderate in severity.12 Approximately 4% of patients discontinue therapy due to toxicity.13 The most common side effects are nausea, vomiting, edema, muscle cramps/pain, diarrhea, and rash. Nausea can be minimized if the dose is taken with food and/or a large glass of water.13 Edema most commonly manifests in the periorbital area or in the lower extremities and is usually ameliorated with diuretics or other supportive care measures.1314 A small percent of patients experience more severe forms of fluid retention (pleural/pericardial effusions, pulmonary edema, ascites, and cerebral edema) and may require interruptions in therapy.14 This is usually dose-related and more common in the elderly and those in blast crisis and accelerated phase CML.13 Skin rashes, which vary greatly in appearance and severity, are commonly controlled with antihistamines or steroids. These topical reactions can be quite severe and are actually the most common reason for termination of imatinib therapy.14

Two additional adverse effects, which occur with lower frequencies but have noteworthy clinical significance, are hepatic and hematological toxicity. Significant liver dysfunction occurs in fewer than 5% of patients and is managed with dose reductions or temporary interruptions in therapy.13 Therefore, liver function tests should be monitored routinely throughout the duration of imatinib therapy.14 Myelosuppression is the most common Grade 3 or 4 adverse event observed in patients being treated with imatinib.15 Marrow suppression may represent a beneficial therapeutic effect, but may also be due to toxicity to normal progenitor cells.14 Neutropenia and thrombocytopenia, the most common manifestations of the marrow suppression, are more common in patients with advanced disease. Colony stimulating factors (filgrastim) have been successfully employed to assist neutrophil recovery and facilitate more sustained administration of imatinib.15

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