Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Allografting

Engraftment syndrome, but not acute GVHD, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic SCT

Bone Marrow Transplantation volume 46, pages 90–97 (2011)Cite this article

Subjects

Abstract

We investigated clinical factors that affected the clearance of tacrolimus (FK506) administered by continuous drip infusion to children who had received allogeneic hematopoietic SCT. Blood FK506 levels were measured every day in 27 patients in an attempt to adjust the dose to maintain the target range (10–15 ng/mL). Patients who developed engraftment syndrome (ES) and acute GVHD and patients less than 7 years of age showed a higher FK506 clearance calculated from body weight (BW) for 5 or more consecutive days compared with the control groups. A time-course study showed that the occurrence of ES, but not acute GVHD, was related to increased clearance of FK506. When calculated from body surface area (BSA), a significant increase in FK506 clearance was observed in patients with ES, but not in those less than 7 years of age. FK506 clearance was not influenced by CYP3A5, multidrug resistance 1 or ABCG2 genotypes. None of the clinical parameters affected blood FK506 levels. Determination of the FK506 dose on the basis of frequent monitoring of the blood concentration seems to minimize the serious adverse effects induced by the immunosuppressant. It may be more accurate to dose FK506 according to BSA rather than BW for pediatric patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Peters DH, Fitton A, Plosker GL, Faulds D . Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746–794.

    Article  CAS  Google Scholar 

  2. Lin CS, Boltz RC, Siekierka JJ, Sigal NH . FK-506 and cyclosporin A inhibit highly similar signal transduction pathways in human T lymphocytes. Cell Immunol 1991; 133: 269–284.

    Article  CAS  Google Scholar 

  3. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 92: 2303–2314.

    CAS  PubMed  Google Scholar 

  4. Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000; 96: 2062–2068.

    CAS  PubMed  Google Scholar 

  5. Hiraoka A, Ohashi Y, Okamoto S, Moriyama Y, Nagao T, Kodera Y et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28: 181–185.

    Article  CAS  Google Scholar 

  6. Wingard JR, Nash RA, Przepiorka D, Klein JL, Weisdorf DJ, Fay JW et al. Relationship of tacrolimus (FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation. Biol Blood Marrow Transplant 1998; 4: 157–163.

    Article  CAS  Google Scholar 

  7. Przepiorka D, Devine S, Fay J, Uberti J, Wingard J . Practical considerations in the use of tacrolimus for allogeneic marrow transplantation. Bone Marrow Transplant 1999; 24: 1053–1056.

    Article  CAS  Google Scholar 

  8. Yanik G, Levine JE, Ratanatharathorn V, Dunn R, Ferrara J, Hutchinson RJ . Tacrolimus (FK506) and methotrexate as prophylaxis for acute graft-versus-host disease in pediatric allogeneic stem cell transplantation. Bone Marrow Transplant 2000; 26: 161–167.

    Article  CAS  Google Scholar 

  9. Przepiorka D, Blamble D, Hilsenbeck S, Danielson M, Krance R, Chan KW . Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transplant 2000; 26: 601–605.

    Article  CAS  Google Scholar 

  10. Mehta P, Beltz S, Kedar A, Graham-Pole J, Wingard JR . Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation. Bone Marrow Transplant 1999; 24: 1323–1327.

    Article  CAS  Google Scholar 

  11. Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002; 74: 571–572.

    Article  CAS  Google Scholar 

  12. Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 2003; 3: 477–483.

    Article  CAS  Google Scholar 

  13. Masuda S, Inui K . An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Ther 2006; 112: 184–198.

    Article  CAS  Google Scholar 

  14. Fukudo M, Yano I, Yoshimura A, Masuda S, Uesugi M, Hosohata K et al. Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients. Pharmacogenet Genomics 2008; 18: 413–423.

    Article  CAS  Google Scholar 

  15. Nakazawa Y, Saito S, Hasegawa Y, Yanagisawa R, Sakashita K, Kamijo T et al. A possible role for the production of multiple HLA antibodies in fatal platelet transfusion refractoriness after peripheral blood progenitor cell transplantation from the mother in a patient with relapsed leukemia. Transfusion 2007; 47: 326–334.

    Article  CAS  Google Scholar 

  16. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  Google Scholar 

  17. Yanagisawa R, Nakazawa Y, Sakashita K, Tanaka M, Shikama N, Kamijo T et al. Low toxicity of a conditioning with 8-Gy total body irradiation, fludarabine and cyclophosphamide as preparative regimen for allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies. Pediatr Transplant 2009; 13: 737–745.

    Article  CAS  Google Scholar 

  18. Cogill JL, Taylor PJ, Westley IS, Morris RG, Lynch SV, Johnson AG . Evaluation of the tacrolimus II microparticle enzyme immunoassay (MEIA II) in liver and renal transplant recipients. Clin Chem 1998; 44: 1942–1946.

    CAS  PubMed  Google Scholar 

  19. Yamazaki T, Masumoto J, Agematsu K, Sawai N, Kobayashi S, Shigemura T et al. Anakinra improves sensory deafness in a Japanese patient with Muckle-Wells syndrome, possibly by inhibiting the cryopyrin inflammasome. Arthritis Rheum 2008; 58: 864–868.

    Article  CAS  Google Scholar 

  20. Miura M, Kagaya H, Satoh S, Inoue K, Saito M, Habuchi T et al. Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Ther Drug Monit 2008; 30: 559–564.

    Article  CAS  Google Scholar 

  21. Boswell GW, Bekersky I, Fay J, Wingard J, Antin J, Weisdorf D et al. Tacrolimus pharmacokinetics in BMT patients. Bone Marrow Transplant 1998; 21: 23–28.

    Article  CAS  Google Scholar 

  22. Wingard JR, Nash RA, Ratanatharathorn V, Fay JW, Klein JL, Przepiorka D et al. Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients. Bone Marrow Transplant 1997; 20: 49–51.

    Article  CAS  Google Scholar 

  23. Spitzer TR . Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 893–898.

    Article  CAS  Google Scholar 

  24. Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989; 143: 718–726.

    CAS  PubMed  Google Scholar 

  25. Fardel O, Lecureur V, Guillouzo A . Regulation by dexamethasone of P-glycoprotein expression in cultured rat hepatocytes. FEBS Lett 1993; 327: 189–193.

    Article  CAS  Google Scholar 

  26. Demeule M, Jodoin J, Beaulieu E, Brossard M, Béliveau R . Dexamethasone modulation of multidrug transporters in normal tissues. FEBS Lett 1999; 442: 208–214.

    Article  CAS  Google Scholar 

  27. Krusekopf S, Roots I, Kleeberg U . Differential drug-induced mRNA expression of human CYP3A4 compared to CYP3A5, CYP3A7 and CYP3A43. Eur J Pharmacol 2003; 466: 7–12.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

    R Yanagisawa, T Shigemura, S Saito, M Tanaka, Y Nakazawa, K Sakashita, M Shiohara & K Koike

  2. Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan

    Y Katsuyama

Authors
  1. R Yanagisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Katsuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Shigemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Sakashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Shiohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Koike
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Koike.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yanagisawa, R., Katsuyama, Y., Shigemura, T. et al. Engraftment syndrome, but not acute GVHD, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic SCT. Bone Marrow Transplant 46, 90–97 (2011). https://doi.org/10.1038/bmt.2010.64

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2010.64

Keywords

This article is cited by

Search

Advanced search

Quick links