Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia

Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients. The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)(CD34+cells)) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration. Early molecular responses were not significantly associated with PK or PD (IC50(CD34+cells)) parameters. However, the PK/PD parameter-time above IC50(CD34+cells)-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50(CD34+cells) achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively). These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50(CD34+cells) could significantly improve prognosis.