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:

Conditioning

Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 53, pages 44–51 (2018)Cite this article

Subjects

Abstract

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5′-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC50) of 3.59 μg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration; therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC50 for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, Bustami RT, Dyke DB . Immunosuppression: practice and trends. Am J Transplant 2004; 4: 38–53.

    Article  Google Scholar 

  2. Minagawa K, Yamamori M, Katayama Y, Matsui T . Mycophenolate mofetil: fully utilizing its benefits for GvHD prophylaxis. Int J Hematol 2012; 96: 10–25.

    Article  CAS  Google Scholar 

  3. Dupuis R, Yuen A, Innocenti F . The influence of UGT polymorphisms as biomarkers in solid organ transplantation. Clinica Chimica Acta 2012; 413: 1318–1325.

    Article  CAS  Google Scholar 

  4. Wieland E, Shipkova M, Schellhaas U, Schutz E, Niedmann PD, Armstrong VW et al. Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects? Clin Biochem 2000; 33: 107–113.

    Article  CAS  Google Scholar 

  5. Patel CG, Ogasawara K, Akhlaghi F . Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus. Xenobiotica 2013; 43: 229–235.

    Article  CAS  Google Scholar 

  6. van Gelder T, Hilbrands LB, Vanrenterghem Y, Weimar W, de Fijter JW, Squifflet JP et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999; 68: 261–266.

    Article  CAS  Google Scholar 

  7. Staatz CE, Tett SE . Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 2007; 46: 13–58.

    Article  CAS  Google Scholar 

  8. Arai Y, Kondo T, Kitano T, Hishizawa M, Yamashita K, Kadowaki N et al. Monitoring mycophenolate mofetil is necessary for the effective prophylaxis of acute GVHD after cord blood transplantation. Bone Marrow Transplant 2015; 50: 312–314.

    Article  CAS  Google Scholar 

  9. Wakahashi K, Yamamori M, Minagawa K, Ishii S, Nishikawa S, Shimoyama M et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol 2011; 94: 193–202.

    Article  CAS  Google Scholar 

  10. Allison AC, Eugui EM . Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000; 47: 85–118.

    Article  CAS  Google Scholar 

  11. Collart FR, Huberman E . Cloning and sequence-analysis of the human and chinese-hamster inosine-5'-monophosphate dehydrogenase cdnas. J Biol Chem 1988; 263: 15769–15772.

    CAS  PubMed  Google Scholar 

  12. Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K . Two distinct cDNAs for human IMP dehydrogenase. J Biol Chem 1990; 265: 5292–5295.

    CAS  PubMed  Google Scholar 

  13. Carr SF, Papp E, Wu JC, Natsumeda Y . Characterization of human type-I and Type-II IMP dehydrogenases. J Biol Chem 1993; 268: 27286–27290.

    CAS  PubMed  Google Scholar 

  14. Li H, Mager DE, Sandmaier BM, Storer BE, Boeckh MJ, Bemer MJ et al. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil. Biol Blood Marrow Transplant 2014; 20: 1121–1129.

    Article  CAS  Google Scholar 

  15. de Winter BCM, Mathot RAA, Sombogaard F, Vulto AG, van Gelder T . Nonlinear relationship between mycophenolate mofetil dose and mycophenolic acid exposure: implications for therapeutic drug monitoring. Clin J Am Soc Nephrol 2011; 6: 656–663.

    Article  CAS  Google Scholar 

  16. Frymoyer A, Verotta D, Jacobson PA, Long-Boyle J . Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic hematopoietic cell transplantation: effect of pharmacogenetic factors. Br J Clin Pharmacol 2013; 75: 463–475.

    Article  CAS  Google Scholar 

  17. Li H, Mager DE, Sandmaier BM, Maloney DG, Bemer MJ, McCune JS . Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil. J Clin Pharmacol 2013; 53: 393–402.

    Article  CAS  Google Scholar 

  18. Barau C, Furlan V, Debray D, Taburet AM, Barrail-Tran A . Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children. Br J Clin Pharmacol 2012; 74: 515–524.

    Article  CAS  Google Scholar 

  19. Kim H, Long-Boyle J, Rydholm N, Orchard PJ, Tolar J, Smith AR et al. Population pharmacokinetics of unbound mycophenolic acid in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation. J Clin Pharmacol 2012; 52: 1665–1675.

    Article  CAS  Google Scholar 

  20. Wang J, Yang JW, Zeevi A, Webber SA, Girnita DM, Selby R et al. IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients. Clin Pharmacol Ther 2008; 83: 711–717.

    Article  CAS  Google Scholar 

  21. Sombogaard F, van Schaik RHN, Mathot RA, Budde K, van der Werf M, Vulto AG et al. Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T > C polymorphism. Pharmacogenet Genom 2009; 19: 626–634.

    Article  CAS  Google Scholar 

  22. Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y . Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 2006; 82: 1074–1084.

    Article  CAS  Google Scholar 

  23. Djebli N, Picard N, Rerolle JP, Le Meur Y, Marquet P . Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on acyl-MPAG production in vitro and in adult renal transplant patients. Pharmacogenet Genom 2007; 17: 321–330.

    Article  CAS  Google Scholar 

  24. Kawanishi M, Yano I, Yoshimura K, Yamamoto T, Hashi S, Masuda S et al. Sensitive and validated LC-MS/MS methods to evaluate mycophenolic acid pharmacokinetics and pharmacodynamics in hematopoietic stem cell transplant patients. Biomed Chromatogr 2015; 29: 1309–1316.

    Article  CAS  Google Scholar 

  25. Savic RM, Jonker DM, Kerbusch T, Karlsson MO . Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharacodyn 2007; 34: 711–726.

    Article  CAS  Google Scholar 

  26. Jiao Z, Ding JJ, Shen J, Liang HQ, Zhong LJ, Wang Y et al. Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9. Br J Clin Pharmacol 2008; 65: 893–907.

    Article  CAS  Google Scholar 

  27. Funaki T . Enterohepatic circulation model for population pharmacokinetic analysis. J Pharm Pharmacol 1999; 51: 1143–1148.

    Article  CAS  Google Scholar 

  28. Karlsson MO, Sheiner LB . The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993; 21: 735–750.

    Article  CAS  Google Scholar 

  29. Yoshimura K, Yano I, Kawanishi M, Nakagawa S, Yonezawa A, Matsubara K . Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats: evaluation of protein binding effects using the modeling and simulation approach. Drug Metab Pharmacoket 2015; 30: 441–448.

    Article  CAS  Google Scholar 

  30. Upton RN, Mould DR . Basic concepts in population modeling, simulation, and model-based drug development: part 3-introduction to pharmacodynamic modeling methods. CPT Pharmacometrics Syst Pharmacol 2014; 3: e88.

    Article  CAS  Google Scholar 

  31. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO . Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J 2011; 13: 143–151.

    Article  Google Scholar 

  32. Beal SL . Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 2001; 28: 481–504.

    Article  CAS  Google Scholar 

  33. Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS et al. The Incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transplant 2016; 22: 605–616.

    Article  Google Scholar 

  34. 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: 353–360.

    Article  CAS  Google Scholar 

  35. Kemmner S, Verbeek M, Heemann U . Renal dysfunction following bone marrow transplantation. J Nephrol 2017; 30: 201–209.

    Article  CAS  Google Scholar 

  36. Sam WJ, Akhlaghi F, Rosenbaum SE . Population pharmacokinetics of mycophenolic acid and its 2 glucuronidated metabolites in kidney transplant recipients. J Clin Pharmacol 2009; 49: 185–195.

    Article  CAS  Google Scholar 

  37. Nowak I, Shaw LM . Mycophenolic-acid binding to human serum-albumin-characterization and relation to pharmacodynamics. Clin Chem 1995; 41: 1011–1017.

    CAS  PubMed  Google Scholar 

  38. Cornell RF, Hari P, Drobyski WR . Engraftment syndrome after autologous stem cell transplantation: an update unifying the definition and management approach. Biol Blood Marrow Transplant 2015; 21: 2061–2068.

    Article  Google Scholar 

  39. Sahin U, Toprak SK, Atilla PA, Atilla E, Demirer T . An overview of infectious complications after allogeneic hematopoietic stem cell transplantation. J Infect Chemother 2016; 22: 505–514.

    Article  Google Scholar 

  40. Nagai M, Natsumeda Y, Weber G . Proliferation-linked regulation of type-II IMP dehydrogenase gene in human normal lymphocytes and HL-60 leukemic-cells. Cancer Res 1992; 52: 258–261.

    CAS  PubMed  Google Scholar 

  41. Nagai M, Natsumeda Y, Konno Y, Hoffman R, Irino S, Weber G . Selective up-regulation of type-II Inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias. Cancer Res 1991; 51: 3886–3890.

    CAS  PubMed  Google Scholar 

  42. Uchida N, Wake A, Nakano N, Ishiwata K, Takagi S, Tsuji M et al. Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. Transplantation 2011; 92: 366–371.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms Machiko Kaneyoshi for her assistant with blood sampling. This study was supported in part by JSPS KAKENHI Grant Number JP25460210.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto, Japan

    K Yoshimura, I Yano, M Kawanishi & A Yonezawa

  2. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan

    K Yoshimura, I Yano, T Yamamoto, M Kawanishi, Y Isomoto, A Yonezawa & K Matsubara

  3. Department of Pharmacy, Kobe University Hospital, Chuo-ku, Kobe, Japan

    I Yano

  4. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan

    T Kondo & A Takaori-Kondo

Authors
  1. K Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Kawanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Isomoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Yonezawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Takaori-Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I Yano.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yoshimura, K., Yano, I., Yamamoto, T. et al. Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 53, 44–51 (2018). https://doi.org/10.1038/bmt.2017.213

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2017.213

Search

Advanced search

Quick links