Clinical Pharmacokinetics of Imatinib Mesylate

This review presents the clinical pharmacokinetics of imatinib mesylate. Aspects regarding absorption, tissue distribution, elimination and kinetic interactions are also discussed. Imatinib (formerly known as STI 571 or CGP 57148B) is a recent oral anticancer agent currently approved in the treatment of Philadelphia chromosome- positive chronic myelogenous leukemia (CML) and metastatic gastro- intestinal stromal tumors (GIST). The rational and quite rapid development of imatinib (3 years between the first clinical trial in patients with CML and the approval in 2001 in the United States), combined with the promising clinical results observed in the treatments of these two rare cancers, has led to extensive literature including several comprehensive reviews (1-8). The aim of this paper was to review the clinical pharmacokinetics of imatinib. Pharmacological properties Imatinib is a 2-phenylaminopyrimidine derivative that acts as an enzyme inhibitor. Imatinib blocks the tyrosine kinase activity of key proteins involved in the pathogenesis of CML and GIST, by inhibiting the binding of adenosine triphosphate (ATP) on the enzyme domain. Hence, imatinib displays activity towards Bcr-Abl, the chimeric protein resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22 (Philadelphia translocation), which is found in 95% of patients with CML. Likewise, imatinib inhibits the deregulated tyrosine activity of the mutated receptor c-kit extensively expressed (85%) in GIST, a subgroup of soft-tissue sarcomas. The mechanism of action of imatinib also includes inhibition of the tyrosine kinase activity of the mutated platelet-derived growth factor