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

Abstract

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 (IC50CD34+cells) parameters. However, the PK/PD parameter—time above IC50CD34+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 IC50CD34+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 IC50CD34+cells could significantly improve prognosis.

DOI: 10.1007/s00228-015-1968-y

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@article{Ishida2015PharmacokineticsAP, title={Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia}, author={Yoji Ishida and Kazunori Murai and Kohei Yamaguchi and Takuto Miyagishima and Motohiro Shindo and Kazuei Ogawa and Takahiro Nagashima and Shinji Sato and Reiko Watanabe and Satoshi Yamamoto and Takayuki Hirose and Souich Saitou and Masakatsu Yonezumi and Takeshi Kondo and Yuichi Kato and Noboru Mochizuki and Keiko Ohno and Satoshi Kishino and Kohmei Kubo and Tatsuo Oyake and Shigeki Ito}, journal={European Journal of Clinical Pharmacology}, year={2015}, volume={72}, pages={185-193} }