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

  • Pharmacokinetics and Disposition
  • Published:
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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 (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).

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 IC50CD34+cells could significantly improve prognosis.

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Acknowledgments

We would like to thank Mrs. H. Chiba and Miss S. Hirayama for their technical assistance. We thank the hematologists Drs. K. Kinoshita, M. Ohta, Y. Okano, Y. Izumiyama, K. Takano, H. Ohgawara, J. Shimono, Izumiguchi, S. Kamihara, S. Kowata, N. Fujimoto, S. Takahashi, J. Yamammoto, T. Chou, K. Wakasa, and H. Karube involved in the IMIDAS clinical study and their clinical staff who kindly provided blood samples, making this analysis possible. We also thank ECRIN, Japan for monitoring the clinical trial.

This work was supported by JSPS KAKENHI Grant Number 25461458.

Authors’ contributions

Y. Ishida designed and performed the experiments, analyzed the data, and wrote the manuscript. K. Murai, K. Yamaguchi, T. Miyagishima, M. Shindo, K. Ogawa, T. Nagashima, S. Sato, R. Watanabe, S. Yamamoto, T. Hirose, S. Saitou, M. Yonezumi, T. Kondo, Y. Kato, K. Kubo, T. Oyake, and S. Ito conducted the clinical trial, provided patient care, and commented on the manuscript. N. Mochizuki, K. Ohno, and S. Kishino measured and analyzed dasatinib pharmacokinetics.

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Authors and Affiliations

  1. Iwate Medical University School of Medicine, Morioka, Japan

    Yoji Ishida, Kazunori Murai, Tatsuo Oyake & Shigeki Ito

  2. Aomori Prefectural Central Hospital, Aomori, Japan

    Kohei Yamaguchi & Kohmei Kubo

  3. Kushiro Rosai Hospital, Kushiro, Japan

    Takuto Miyagishima

  4. Asahikawa Medical University School of Medicine, Asahikawa, Japan

    Motohiro Shindo

  5. Fukushima Medical University School of Medicine, Fukushima, Japan

    Kazuei Ogawa

  6. Kitami Red Cross Hospital, Kitami, Japan

    Takahiro Nagashima

  7. Okitama Public General Hospital, Higashi-Okitama, Japan

    Shinji Sato

  8. Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

    Reiko Watanabe

  9. Sapporo City General Hospital, Sapporo, Japan

    Satoshi Yamamoto

  10. Niigata Cancer Center Hospital, Niigata, Japan

    Takayuki Hirose

  11. Nihonkai General Hospital, Sakata, Japan

    Souich Saitou

  12. Hokkaido Cancer Center, Sapporo, Japan

    Masakatsu Yonezumi

  13. Hokkaido University School of Medicine, Sapporo, Japan

    Takeshi Kondo

  14. Yamagata University Faculty of Medicine, Yamagata, Japan

    Yuichi Kato

  15. Meiji Pharmaceutical University, Kiyose, Japan

    Noboru Mochizuki, Keiko Ohno & Satoshi Kishino

  16. Department of Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, 19-1, Uchimaru, Morioka, Iwate, 020-8505, Japan

    Yoji Ishida

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  1. Yoji Ishida
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  2. Kazunori Murai
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the Inter-Michinoku Dasatinib Study Group (IMIDAS)

Corresponding author

Correspondence to Yoji Ishida.

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Conflict of interest disclosures

Y. Ishida received honorarium and speaker fee from Bristol-Myers.

The remaining authors declare no conflict of interest.

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Ishida, Y., Murai, K., Yamaguchi, K. et al. Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia. Eur J Clin Pharmacol 72, 185–193 (2016). https://doi.org/10.1007/s00228-015-1968-y

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  • DOI: https://doi.org/10.1007/s00228-015-1968-y

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