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Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation

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Abstract

Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC0–24h). In allo-BMT, high AUC0–24h (>30 μg h/ml) resulted in no incidence of grade II–IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC0–24h less than 30 μg h/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC0–24h and C2h, plasma MPA concentration at 2 h after administration was observed. Single point assessment of C2h was shown to provide a useful surrogate of AUC0–24h to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.

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Acknowledgments

This work was supported, in part, by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare, and Labor in Japan.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Kanako Wakahashi, Kentaro Minagawa, Shinichi Ishii, Shinichirou Nishikawa, Manabu Shimoyama, Hiroki Kawano, Yuko Kawano, Yuriko Kawamori, Akiko Sada, Toshimitsu Matsui & Yoshio Katayama

  2. Department of Clinical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, Nishinomiya, Japan

    Motohiro Yamamori

Authors
  1. Kanako Wakahashi
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  2. Motohiro Yamamori
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  3. Kentaro Minagawa
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  4. Shinichi Ishii
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  5. Shinichirou Nishikawa
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  6. Manabu Shimoyama
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  7. Hiroki Kawano
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  9. Yuriko Kawamori
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  11. Toshimitsu Matsui
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  12. Yoshio Katayama
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Corresponding author

Correspondence to Kentaro Minagawa.

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Wakahashi, K., Yamamori, M., Minagawa, K. et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol 94, 193–202 (2011). https://doi.org/10.1007/s12185-011-0888-6

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  • DOI: https://doi.org/10.1007/s12185-011-0888-6

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