Skip to main content

Advertisement

Log in

Comparison of high-performance liquid chromatography and enzyme-multiplied immunoassay technique to monitor mycophenolic acid in paediatric renal recipients

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) is recommended to guide immunosuppression. High-performance liquid chromatography with ultraviolet (HPLC-UV) or the enzyme-multiplied immunoassay technique (EMIT), used to measure mycophenolic acid (MPA) were compared in an exclusive paediatric renal transplant population. Twenty patients were included as part of the pharmacokinetics study of MMF, and 88 additional samples were drawn for TDM. Agreement between HPLC-UV and EMIT was assessed by the Bland–Altman method. With the two methods, pre-dose concentrations were not normally distributed. After logarithmic transformation, their mean was 0.79 ± 1.16 μg  ml−1 and their mean difference was 0.34 ± 0.16 μg ml−1 [95% confidence interval (95%CI 0.30–0.38 μg ml−1, with antilogarithmic values of these limits of 1.34–1.46 μg ml−1). Area under the curve (AUC)HPLC and AUCEMIT were normally distributed. Their mean was 52.42 ± 25.91 mg × h/l and their mean difference was 15.22 ± 8 mg × h/l (95%CI 11.99–18.45 mg × h/l), the Bland–Altman plot showing a bias proportional to the mean. Our data showed the absence of agreement between the HPLC and EMIT methods, with an average positive bias of 15% with the EMIT. Further studies are required to determine which method is best appropriate for TDM of MMF in children.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. European Mycophenolate Mofetil Cooperative Study Group (1995) Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 345:1321–1325

    Google Scholar 

  2. The US Mycophenolate Mofetil Cooperative Study Group (1997) Mycophenolate mofetil for the prevention of acute rejection of primary cadaveric kidney transplants: status of the MYC 1866 study at 1 year. Transplant Proc 29:348–349

    Google Scholar 

  3. Staatz CE, Tell SA (2007) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 46:13–58

    CAS  PubMed  Google Scholar 

  4. Ettenger R, Sarwal MM (2005) Mycophenolate mofetil in paediatric renal transplantation. Transplantation 80 [Suppl 2]:s201–s210

    CAS  PubMed  Google Scholar 

  5. Offermann G (2003) Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil. Clin Transplant 17:43–46

    PubMed  Google Scholar 

  6. Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429–455

    CAS  PubMed  Google Scholar 

  7. Allison AC (2005) Mechanism of action of mycophenolate mofetil. Lupus 14 [Suppl 1]:s2–s8

    CAS  PubMed  Google Scholar 

  8. Schutz E, Shipkova M, Armstrong VW, Wieland E, Oellerich M (1999) Identification of a pharmacologically active metabolite of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Clin Chem 45:419–422

    CAS  PubMed  Google Scholar 

  9. Shipkova M, Wieland E, Schutz E, Wiese C, Niedmann PD, Oellerich M, Armstrong VW (2001) The acyl glucuronide metabolite of mycophenolic acid inhibits the proliferation of human mononuclear leukocytes. Transplant Proc 33:1080–1081

    CAS  PubMed  Google Scholar 

  10. Payen S, Zhang D, Maisin A, Popon M, Bensman A, Bouissou F, Loirat C, Gomeni R, Bressolle F, Jacqz-Aigrain E (2005) Population pharmacokinetics of mycophenolic acid in kidney transplant pediatric and adolescent patients. Ther Drug Monit 27:378–388

    CAS  PubMed  Google Scholar 

  11. Staatz CE, Dufull SB, Kiberd B, Fraser AD, Tett SE (2005) Population pharmacokinetics of mycophenolic acid during the first week after transplantation. Eur J Clin Pharmacol 61:507–516

    CAS  PubMed  Google Scholar 

  12. Le Guellec C, Bourgoin H, Buchler M, Le Meur Y, Lebranchu Y, Marquet P, Paintaud G (2004) Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients. Clin Pharmacokinet 43:253–266

    PubMed  Google Scholar 

  13. Weber LT, Shipkova M, Lamersdorf T, Niedmann PD, Wiesel M, Mandelbaum A, Zimmerhackl LB, Schutz E, Mehls O, Oellerich M, Armstrog VW, Tonshoff B (1998) Pharmacokinetics of mycophenolic acid (MPA) and determination of MPA free fraction in paediatric and adult renal transplant recipients. German Study group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. J Am Soc Nephrol 9:1511–1520

    CAS  PubMed  Google Scholar 

  14. van Gelder T, Meur YL, Shaw LM, Oellerich M, DeNofrio D, Holt C, Holt DW, Kaplan B, Kuypers D, Meiser B, Toenshoff B, Mamelok RD (2006) Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 28:145–154

    PubMed  Google Scholar 

  15. Filler G (2006) Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation. Pediatr Transplant 10:707–711

    CAS  PubMed  Google Scholar 

  16. Ghio L, Ferraresso M, Vigano SM, Ginevri F, Perfumo F, Gianoglio B, Murer L, Zacchello G, Dello Strologo L, Cardillo M, Tirelli S, Valente U, Edefonti A (2005) Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients. Transplant Proc 37:857–858

    Google Scholar 

  17. Beal JL, Jones CE, Taylor PJ, Tett SE (1998) Evaluation of an immunoassay (EMIT) for mycophenolic acid in plasma from renal transplant recipients compared with a high-performance liquid chromatography assay. Ther Drug Monit 20:685–690

    CAS  PubMed  Google Scholar 

  18. Schutz E, Shipkova M, Armstrong VW, Niedmann PD, Weber L, Tonshoff B, Pethig K, Wahlers T, Braun F, Ringe B, Oellerich M (1998) Therapeutic drug monitoring of mycophenolic acid: comparison of HPLC and immunoassay reveals new MPA metabolites. Transplant Proc 30:1185–1877

    CAS  PubMed  Google Scholar 

  19. Shipkova M, Schutz E, Armstrong VW, Niedmann PD, Wieland E, Oellerich M (1999) Overestimation of mycophenolic acid by EMIT correlates with MPA metabolite. Transplant Proc 31:1135–1137

    CAS  PubMed  Google Scholar 

  20. Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1:307–310

    CAS  Google Scholar 

  21. Bland JM, Altman DG (1995) Comparing methods of measurement: why plotting difference against standard method is misleading. Lancet 346:1085–1087

    CAS  PubMed  Google Scholar 

  22. Fisher MB, Paisne MF, Strelevitz TJ, Wrighton SA (2001) The role of hepatic and extrahepatic UDP-glucuronidation in human drug metabolism. Drug Metab Rev 33:273–297

    CAS  PubMed  Google Scholar 

  23. Levesque E, Delage R, Benoist-Biancamano MO, Caron P, Bernard O, Couture F, Guillemette C (2007) The impact of UGT1A8, UGT1A9 and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single dose in healthy volunteers. Clin Pharmacol Ther 81:392–400

    CAS  PubMed  Google Scholar 

  24. Kiberd BA, Lawen J, Fraser AD, Keough-Ryan T, Belitskt P (2004) Early adequate mycophenolic acid exposure is associated with less rejection in kidney transplantation. Am J Transplant 4:1079–1083

    CAS  PubMed  Google Scholar 

  25. Nicholls AJ (1998) Opportunities for therapeutic monitoring of mycophenolate mofetil dose in renal transplantation suggested by the pharmacokinetic/pharmacodynamic relationship for mycophenolate mofetil and suppression of rejection. Clin Biochem 31:329–333

    CAS  PubMed  Google Scholar 

  26. LeMeur Y, Buchler M, Thierry A, Caillard S, Villemain F, Lavaud S, Etienne I, Westeel PF, de Ligny BH, Rostaing L, Thervet E, Szelag JC, Rerolle JP, Rousseau A, Touchard G, Marquet P (2007) Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patent outcome after renal transplantation. Am J Transplant 7:2496–2503

    CAS  Google Scholar 

  27. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167

    CAS  PubMed  Google Scholar 

  28. Filler G, Foster J, Berard R, Mai I, Lepage N (2004) Age-dependency of mycophenolate dosing in combination with tacrolimus after pediatric transplantation. Transplant Proc 36:1327–1331

    CAS  PubMed  Google Scholar 

  29. Shaw LM, Holt DW, Oellerich M, Meiser B, Van Gelder T (2001) Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit 23:305–315

    CAS  PubMed  Google Scholar 

  30. Pape L, Ehrich JH, Offner G (2004) Long term follow-up of pediatric transplant recipients: mycophenolic acid through levels are not a good indicator for long-term graft function. Clin Transplant 18:576–579

    CAS  PubMed  Google Scholar 

  31. David-Neto E, Montiero Pereira Araujo L, Sumita NM, Mendes ME, Ribeiro Castro MC, Alves CF, Kakehashi E, Romano P, Yagyu EM, Queiroga M, Nahas WC, Ianhez LE (2003) Mycophenolic acid pharmacokinetics in stable pediatric renal transplantation. Pediatr Nephrol 18:266–272

    PubMed  Google Scholar 

  32. Filler G (2004) Abbreviated mycophenolic acid AUC from C0, C1, C2 and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int 17:120–125

    CAS  PubMed  Google Scholar 

  33. Premaud A, Rousseau A, Le Meur Y, Lachatre G, Marquet P (2004) Comparison of liquid chromatography-tandem mass spectrometry with a commercial enzyme-multiplied immunoassay for the determination of plasma MPA in renal transplant recipients and consequences for therapeutic drug monitoring. Ther Drug Monit 26:609–619

    CAS  PubMed  Google Scholar 

  34. Weber LT, Shipkova M, Armstrong VW, Wagner N, Schutz E, Mehls O, Zimmerhackl LB, Oellerich M, Tonshoff B (2002) Comparison of the EMIT immunoassay with HPLC for therapeutic drug monitoring of mycophenolic acid in pediatric renal-transplant recipients on mycophenolate mofetil therapy. Clin Chem 48:517–525

    CAS  PubMed  Google Scholar 

  35. Jacqz-Aigrain E, Khan-Shaghaghi E, Baudouin V, Popon M, Zhang D, Maisin A, Loirat C (2000) Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children. Pediatr Nephrol 14:95–99

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Évelyne Jacqz-Aigrain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Irtan, S., Azougagh, S., Monchaud, C. et al. Comparison of high-performance liquid chromatography and enzyme-multiplied immunoassay technique to monitor mycophenolic acid in paediatric renal recipients. Pediatr Nephrol 23, 1859–1865 (2008). https://doi.org/10.1007/s00467-008-0877-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-008-0877-z

Keywords

Navigation