Yoji Ishida1,2, Kazunori Murai3, Kohei Yamaguchi4, Takuto Miyagishima5, Motohiro Shindo6, Kazuei Ogawa7, Takahiro Nagashima8, Shinji Sato9, Reiko Watanabe10, Satoshi Yamamoto11, Takayuki Hirose12, Souich Saitou13, Masakatsu Yonezumi14, Takeshi Kondo15, Yuichi Kato16, Noboru Mochizuki17, Keiko Ohno17, Satoshi Kishino17, Kohmei Kubo4, Tatsuo Oyake3, Shigeki Ito3. 1. Iwate Medical University School of Medicine, Morioka, Japan. yishida@iwate-med.ac.jp. 2. Department of Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, 19-1, Uchimaru, Morioka, Iwate, 020-8505, Japan. yishida@iwate-med.ac.jp. 3. Iwate Medical University School of Medicine, Morioka, Japan. 4. Aomori Prefectural Central Hospital, Aomori, Japan. 5. Kushiro Rosai Hospital, Kushiro, Japan. 6. Asahikawa Medical University School of Medicine, Asahikawa, Japan. 7. Fukushima Medical University School of Medicine, Fukushima, Japan. 8. Kitami Red Cross Hospital, Kitami, Japan. 9. Okitama Public General Hospital, Higashi-Okitama, Japan. 10. Saitama Medical Center, Saitama Medical University, Kawagoe, Japan. 11. Sapporo City General Hospital, Sapporo, Japan. 12. Niigata Cancer Center Hospital, Niigata, Japan. 13. Nihonkai General Hospital, Sakata, Japan. 14. Hokkaido Cancer Center, Sapporo, Japan. 15. Hokkaido University School of Medicine, Sapporo, Japan. 16. Yamagata University Faculty of Medicine, Yamagata, Japan. 17. Meiji Pharmaceutical University, Kiyose, Japan.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
PURPOSE: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 leukemiapatients. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
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