Indications
Imatinib is indicated for the treatment of adult and pediatric patients with chronic myeloid leukemia characterized by the Philadelphia chromosome mutation (Ph+). It is particularly useful in cases experiencing blast crisis, accelerated phase, or chronic phase following the failure of IFN-alpha therapy. Beyond its application in chronic myeloid leukemia, imatinib is also prescribed for adult and pediatric patients with Ph+ acute lymphoblastic leukemia. It further extends to treat adults with myelodysplastic or myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST).
Pharmacodynamics
Imatinib functions as a neoplastic agent derived from 2-phenylaminopyrimidine, belonging to the class of tyrosine kinase inhibitors. It exhibits a relatively selective inhibition towards the BCR-ABL fusion protein, which is implicated in various cancers. The BCR-ABL pathway regulates several downstream pathways integral to neoplastic growth, including the Ras/MapK pathway (associated with cellular proliferation), the Src/Pax/Fak/Rac pathway (involved in cellular motility), and the PI/PI3K/AKT/BCL-2 pathway (related to the apoptosis pathway). Targeting the BCR-ABL pathway presents a valuable approach in cancer treatment. While normal cells also utilize these pathways, they are less impacted by imatinib due to the presence of redundant tyrosine kinases that enable continued function despite ABL inhibition. Conversely, cancer cells can exhibit a dependency on BCR-ABL, making them more susceptible to the effects of imatinib.
Absorption
Imatinib is efficiently absorbed following oral administration, with the peak concentration (Cmax) reached within 2 to 4 hours post-dose. It displays an average absolute bioavailability of 98%. The mean area under the curve (AUC) for imatinib increases proportionately with doses ranging from 25 mg to 1,000 mg. Notably, the pharmacokinetics of imatinib remain consistent upon repeated dosing, with accumulation observed to be 1.5- to 2.5-fold at steady state when dosed once daily.
Metabolism
The metabolism of imatinib is predominantly mediated by the enzyme CYP3A4. Other cytochrome P450 enzymes, including CYP1A2, CYP2D6, CYP2C9, and CYP2C19, contribute to its metabolism to a lesser extent. The primary circulating active metabolite in humans is the N-demethylated piperazine derivative, which is mainly produced by CYP3A4 and exhibits in vitro potency comparable to the original imatinib compound.
Mechanism of Action
Imatinib functions as a protein-tyrosine kinase inhibitor, targeting the BCR-ABL tyrosine kinase-a constitutively active kinase resulting from the Philadelphia chromosome anomaly in chronic myeloid leukemia (CML). Although the role of normal BCR remains somewhat unclear, the activation of ABL is markedly overexpressed in various tumors, playing a crucial role in the proliferation and survival of cancer cells. Imatinib effectively inhibits the BCR-ABL protein by binding to the ATP-binding site on the active enzyme, thereby obstructing the subsequent phosphorylation of target proteins. Moreover, imatinib acts as an inhibitor of receptor tyrosine kinases, including those for platelet-derived growth factor (PDGF) and stem cell factor (SCF), such as c-Kit. It impedes cellular processes mediated by PDGF and SCF. In vitro studies demonstrate that imatinib suppresses cell proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which exhibit an activating mutation in c-Kit.
