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1. Pharmacologic Properties
Dasatinib (Sprycel®) is an orally administered second-generation tyrosine kinase inhibitor, structurally unrelated to the first-generation agent imatinib.[1] It inhibits the activity of the oncogenic kinases BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, ephrin A receptor, and platelet-derived growth factor β receptor (PDGFR-β) at nanomolar concentrations.[1]
The constitutively activated BCR-ABL kinase, which plays a central role in the development of and is characteristic of chronic myeloid leukemia (CML), derives from the aberrant Philadelphia (Ph) chromosome formed by a reciprocal translocation t(9;22)(q34;q11) that fuses the ABL receptor tyrosine kinase gene from chromosome 9 to the BCR gene on chromosome 22.[2,3] Dasatinib antagonizes and switches off the downstream BCR-ABL-activated intracellular signaling pathways that are associated with most of the leukemogenic effects of the kinase, including those required for cell-cycle progression, the induction of apoptosis, cell proliferation, and adhesion.[4]
In vitro, dasatinib is [approximate]325-fold more potent than imatinib and [approximate]16-fold more potent than nilotinib at inhibiting proliferation of cell lines expressing wild-type BCR-ABL.[5,6] Dasatinib appears to bind to and stabilize a different conformation of the BCR-ABL kinase enzyme to those stabilized by imatinib and nilotinib.[7]
Dasatinib is active in vitro in both imatinib-sensitive and imatinib-resistant Ph+ leukemic cell lines, with the exception of those with the T315I mutation in the BCR-ABL kinase domain, which is unresponsive to all available tyrosine kinase inhibitors.[1,8]
Oral dasatinib is rapidly absorbed, reaching peak plasma concentrations 0.5-3 hours after administration.[6] Exposure is unaffected by food intake, so dasatinib is taken without regard to food. Dasatinib crosses the blood-brain barrier, achieving therapeutic concentrations in the CNS.[9] Dasatinib is metabolized in the liver, predominantly by cytochrome P450 3A4, to effectively inactive metabolites, and is excreted mainly in feces. The terminal elimination half-life is approximately 5-6 hours.[6]
2. Therapeutic Efficacy
Dasatinib was more effective than imatinib in treating newly diagnosed patients with chronic-phase CML.[10,11] Cytogenetic and molecular responses were significantly greater with dasatinib than imatinib at 1 year, although the estimated 12-month rates of progression-free survival (PFS) and overall survival (OS) did not differ - both were close to maximal in each treatment arm. Consequently, once-daily dasatinib has now been approved for use as first-line therapy in newly diagnosed patients with chronic-phase CML, as well as for use after failure of...