Dasatinib: Is it all in the dose?

Dasatinib is approved for the treatment of chronic myeloid leukemia (CML) in patients with resistance or intolerance to imatinib. This article reviews pharmacokinetic, pharmacodynamic, and clinical data on dasatinib, and highlights some of the most important issues that need to be addressed.Imatinib and dasatinib both target the tyrosine kinase activity of the BCRABL oncogenic fusion protein. In terms of pharmacodynamics, the two agents differ in several ways: (i) dasatinib is >300-fold more potent than imatinib in inhibiting BCRABL activity; (ii) inhibition profiles on other tyrosine kinases differ between imatinib and dasatinib; and (iii) dasatinib has other peculiar effects on the leukemogenic signaling, including activation of p38 mitogen-activated protein kinase (MAPK) and reduction of the apoptotic-inactive form of the BCL2-associated agonist of cell death (BAD) protein. Recent pharmacodynamic data suggested combination therapy with dasatinib and signaling inhibitors (e.g. flavopiridol, farnesyl transferase inhibitors, or histone deacetylase inhibitors) may be beneficial.In contrast to other tyrosine kinase inhibitors (TKIs), dasatinib has a reduced half-life and no active metabolites.In a randomized, open-label, phase III trial, dasatinib 100mg once daily demonstrated similar efficacy and a better tolerability profile than 70mg twice daily. This unexpected result has been confirmed in recent studies, in which a dose of dasatinib 100mg once daily was sufficient to trigger apoptosis in leukemic cells. Furthermore, cytogenetic responses correlate with BCRABL inhibition.Data suggest dasatinib 100mg once daily achieves oncogenic shock and chronic inhibition of BCRABL activity, suggesting that in the future, pulse therapy with TKIs may be an option in some specific patients with CML.