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Pharmacokinetics-based optimal dose-exploration of mycophenolate mofetil in allogeneic hematopoietic stem cell transplantation

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Abstract

For better clinical outcomes of mycophenolate mofetil (MMF) in allogeneic hematopoietic stem cell transplantation (alloSCT), higher mycophenolic acid (MPA) plasma levels are proposed to be desirable. Here, we investigate the optimal MMF dosing strategy based on pharmacokinetic studies in 20 Japanese alloSCT patients. The first 11 patients received MMF twice daily at an escalated dose from 15 mg/kg, according to real-time pharmacokinetic monitoring of the total MPA area under the curve (AUC). In the subsequent nine patients, MMF was given at a fixed dose of 1,000 mg three-times daily. The pharmacokinetic data revealed that the dose escalation in each individual did not always increase the AUC. In contrast, the increase of dosing frequency could statistically keep higher MPA plasma levels, as reflected in higher concentration at steady state (C ss) or trough value (C trough). There was no symptomatic adverse event in both groups. These results suggest that MMF administration of every 8 h after alloSCT would be better to maintain higher MPA plasma levels than that of every 12 h even in the same daily dose. Further studies are necessary to confirm the clinical benefit of MMF to prevent graft failure, as well as severe aGVHD.

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References

  1. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science. 1999;285:412–5.

    Article  CAS  PubMed  Google Scholar 

  2. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001;411:385–9.

    Article  CAS  PubMed  Google Scholar 

  3. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729–35.

    Article  CAS  PubMed  Google Scholar 

  4. Vogelsang GB, Arai S. Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings. Bone Marrow Transplant. 2001;27:1255–62.

    Article  CAS  PubMed  Google Scholar 

  5. Zeiser R, Marks R, Bertz H, Finke J. Immunopathogenesis of acute graft-versus-host disease: implications for novel preventive and therapeutic strategies. Ann Hematol. 2004;83:551–65.

    Article  CAS  PubMed  Google Scholar 

  6. Bacigalupo A. Management of acute graft-versus-host disease. Br J Haematol. 2007;137:87–98.

    Article  CAS  PubMed  Google Scholar 

  7. Bolwell B, Sobecks R, Pohlman B, Andresen S, Rybicki L, Kuczkowski E, et al. A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;34:621–5.

    Article  CAS  PubMed  Google Scholar 

  8. Neumann F, Graef T, Tapprich C, Vaupel M, Steidl U, Germing U, et al. Cyclosporine A and mycophenolate mofetil vs cyclosporine A and methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings. Bone Marrow Transplant. 2005;35:1089–93.

    Article  CAS  PubMed  Google Scholar 

  9. Kawamori Y, Yakushi** K, Okamura A, Nishikawa S, Minagawa K, Shimoyama M, et al. Successful engraftment in reduced-intensity cord blood transplantation (CBT) as a salvage therapy for graft failure after primary CBT in adults. Transplantation. 2007;83:1281–2.

    Article  PubMed  Google Scholar 

  10. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet. 1998;34:429–55.

    Article  CAS  PubMed  Google Scholar 

  11. van Hest RM, Doorduijn JK, de Winter BC, Cornelissen JJ, Vulto AG, Oellerich M, et al. Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients. Ther Drug Monit. 2007;29:353–60.

    Article  PubMed  Google Scholar 

  12. Ng J, Rogosheske J, Barker J, Weisdorf D, Jacobson PA. A limited sampling model for estimation of total and unbound mycophenolic acid (MPA) area under the curve (AUC) in hematopoietic cell transplantation (HCT). Ther Drug Monit. 2006;28:394–401.

    Article  CAS  PubMed  Google Scholar 

  13. Shaw LM, Holt DW, Oellerich M, Meiser B, van Gelder T. Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit. 2001;23:305–15.

    Article  CAS  PubMed  Google Scholar 

  14. Osunkwo I, Bessmertny O, Harrison L, Cheung YK, Van de Ven C, del Toro G, et al. A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant. 2004;10:246–58.

    Article  CAS  PubMed  Google Scholar 

  15. Jacobson P, Rogosheske J, Barker JN, Green K, Ng J, Weisdorf D, et al. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther. 2005;78:486–500.

    Article  CAS  PubMed  Google Scholar 

  16. Giaccone L, McCune JS, Maris MB, Gooley TA, Sandmaier BM, Slattery JT, et al. Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation. Blood. 2005;106:4381–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maris MB, Sandmaier BM, Storer BE, Maloney DG, Shizuru JA, Agura E, et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant. 2006;12:454–65.

    Article  CAS  PubMed  Google Scholar 

  18. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  19. Van Gelder T, Klupp J, Barten MJ, Christians U, Morris RE. Co-administration of tacrolimus and mycophenolate mofetil does not increase mycophenolic acid (MPA) exposure, but co-administration of cyclosporine inhibits the enterohepatic recirculation of MPA, thereby decreasing its exposure. J Heart Lung Transplant. 2001;20:160–1.

    Article  PubMed  Google Scholar 

  20. Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT, et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2005;11:495–505.

    Article  CAS  PubMed  Google Scholar 

  21. Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89:3048–54.

    CAS  PubMed  Google Scholar 

  22. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390–400.

    Article  CAS  PubMed  Google Scholar 

  23. Kobbe G, Schneider P, Aivado M, Zohren F, Schubert D, Fenk R, et al. Reliable engraftment, low toxicity, and durable remissions following allogeneic blood stem cell transplantation with minimal conditioning. Exp Hematol. 2002;30:1346–53.

    Article  PubMed  Google Scholar 

  24. Kiehl MG, Schafer-Eckart K, Kroger M, Bornhauser M, Basara N, Blau IW, et al. Mycophenolate mofetil for the prophylaxis of acute graft-versus-host disease in stem cell transplant recipients. Transplant Proc. 2002;34:2922–4.

    Article  CAS  PubMed  Google Scholar 

  25. Bornhauser M, Schuler U, Porksen G, Naumann R, Geissler G, Thiede C, et al. Mycophenolate mofetil and cyclosporine as graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation. Transplantation. 1999;67:499–504.

    Article  CAS  PubMed  Google Scholar 

  26. Nieto Y, Patton N, Hawkins T, Spearing R, Bearman SI, Jones RB, et al. Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation. Biol Blood Marrow Transplant. 2006;12:217–25.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are very grateful to the patients who participated in this study. The authors also would like to thank all the nurses, other medical staff of the stem cell transplantation unit, and physicians of Hematology Division at Kobe University Hospital for taking care of our patients in this study. This work was supported in part by Grants-in-Aid for scientific Research from the Ministry of Health, Welfare, and Labor in Japan.

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Authors and Affiliations

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

    Atsuo Okamura, Manabu Shimoyama, Yuko Kawano, Hiroki Kawano, Yuriko Kawamori, Shinichiro Nishikawa, Kentaro Minagawa, Kimikazu Yakushi**, Yoshio Katayama & Toshimitsu Matsui

  2. Department of Hospital Pharmacy, Kobe University Hospital, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Motohiro Yamamori, Toshiyuki Sakaeda & Midori Hirai

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  1. Atsuo Okamura
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  2. Motohiro Yamamori
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  3. Manabu Shimoyama
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  4. Yuko Kawano
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  5. Hiroki Kawano
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  6. Yuriko Kawamori
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  9. Kimikazu Yakushi**
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  10. Yoshio Katayama
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  11. Toshiyuki Sakaeda
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  12. Midori Hirai
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  13. Toshimitsu Matsui
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Correspondence to Toshimitsu Matsui.

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Okamura, A., Yamamori, M., Shimoyama, M. et al. Pharmacokinetics-based optimal dose-exploration of mycophenolate mofetil in allogeneic hematopoietic stem cell transplantation. Int J Hematol 88, 104–110 (2008). https://doi.org/10.1007/s12185-008-0093-4

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  • DOI: https://doi.org/10.1007/s12185-008-0093-4

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