Seminars in Arthritis and Rheumatism
Volume 40, Issue 4 , Pages 307-313 , February 2011

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

  • Anna Carmela P. Sagcal-Gironella, MD, MS

      Affiliations

    • Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • ,
  • Tsuyoshi Fukuda, PhD

      Affiliations

    • Division of Clinical Pharmacology and Pediatric Pharmacology Research Unit (PPRU), Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH
    • ,
  • Kristina Wiers, MD, MS

      Affiliations

    • Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • ,
  • Shareen Cox, BS

      Affiliations

    • Division of Clinical Pharmacology and Pediatric Pharmacology Research Unit (PPRU), Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • ,
  • Shannen Nelson, MSN, RN

      Affiliations

    • Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • ,
  • Blair Dina, BS

      Affiliations

    • Division of Rheumatology, Children's Memorial Hospital, Chicago, IL
    • ,
  • Catherine M.T. Sherwin, PhD, BSc(Hons)

      Affiliations

    • Division of Clinical Pharmacology and Pediatric Pharmacology Research Unit (PPRU), Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • ,
  • Marisa S. Klein-Gitelman, MD, MPH

      Affiliations

    • Division of Rheumatology, Children's Memorial Hospital, Chicago, IL
    • ,
  • Alexander A. Vinks, PharmD, PhD

      Affiliations

    • Division of Clinical Pharmacology and Pediatric Pharmacology Research Unit (PPRU), Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH
    • ,
  • Hermine I. Brunner, MD, MSc

      Affiliations

    • Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    • Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH
    • Corresponding Author InformationAddress reprint requests to: Hermine I. Brunner, MD, MSc, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4010, Cincinnati, OH 45229-3039

References 

  1. Morris RE, Hoyt EG, Murphy MP, Eugui EM, Allison AC. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc. 1990;22(4):1659–1662
  2. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47(2-3):85–118
  3. Allison AC, Eugui EM. Preferential suppression of lymphocyte proliferation by mycophenolic acid and predicted long-term effects of mycophenolate mofetil in transplantation. Transplant Proc. 1994;26(6):3205–3210
  4. Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit. 1995;17(6):681–684
  5. Chaigne-Delalande B, Guidicelli G, Couzi L, Merville P, Mahfouf W, Bouchet S, et al. The immunosuppressor mycophenolic acid kills activated lymphocytes by inducing a nonclassical actin-dependent necrotic signal. J Immunol. 2008;181(11):7630–7638
  6. Alba P, Karim MY, Hunt BJ. Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus. 2003;12(8):633–635
  7. Vasoo S, Thumboo J, Fong KY. Refractory immune thrombocytopenia in systemic lupus erythematosus: response to mycophenolate mofetil. Lupus. 2003;12(8):630–632
  8. Schanz S, Ulmer A, Rassner G, Fierlbeck G. Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil. Br J Dermatol. 2002;147(1):174–178
  9. Gaubitz M, Schorat A, Schotte H, Kern P, Domschke W. Mycophenolate mofetil for the treatment of systemic lupus erythematosus: an open pilot trial. Lupus. 1999;8(9):731–736
  10. Falcini F, Capannini C, Martini M, La Torre L, Vitale V, Nacci N, et al. Mycophenolate mofetil (MMF) for the treatment of juvenile onset systemic lupus erythematosus. Pediatr Rheumatol. 2008;6(Suppl 1):P234
  11. Tannuri U, Gibelli NE, Maksoud-Filho JG, Santos MM, Pinho-Apezzato ML, Velhote MC, et al. Mycophenolate mofetil promotes prolonged improvement of renal dysfunction after pediatric liver transplantation: experience of a single center. Pediatr Transplant. 2007;11(1):82–86
  12. Jungraithmayr TC, Wiesmayr S, Staskewitz A, Kirste G, Bulla M, Fehrenbach H, et al. Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation. Transplantation. 2007;83(7):900–905
  13. Cransberg K, Cornelissen M, Lilien M, Van Hoeck K, Davin JC, Nauta J. Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk. Transplantation. 2007;83(8):1041–1047
  14. Ojogho O, Sahney S, Cutler D, Baron PW, Abdelhalim FM, James S, et al. Mycophenolate mofetil in pediatric renal transplantation: non-induction vs. induction with basiliximab. Pediatr Transplant. 2005;9(1):80–83
  15. Lobritto SJ, Rosenthal P, Bouw R, Leung M, Snell P, Mamelok RD. Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine. Liver Transpl. 2007;13(11):1570–1575
  16. Ettenger R, Cohen A, Nast C, Moulton L, Marik J, Gales B. Mycophenolate mofetil as maintenance immunosuppression in pediatric renal transplantation. Transplant Proc. 1997;29(1-2):340–341
  17. Hocker B, Weber LT, Bunchman T, Rashford M, Tonshoff B. Mycophenolate mofetil suspension in pediatric renal transplantation: three-year data from the tricontinental trial. Pediatr Transplant. 2005;9(4):504–511
  18. Cattaneo D, Perico N, Gaspari F, Gotti E, Remuzzi G. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int. 2002;62(3):1060–1067
  19. Sherwin C, Fukuda T, Goebel J, Brunner HI, Vinks AA. The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2009;(in press)
  20. Le Meur Y, Buchler M, Thierry A, Caillard S, Villemain F, Lavaud S, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7(11):2496–2503
  21. Jeong H, Kaplan B. Therapeutic monitoring of mycophenolate mofetil. Clin J Am Soc Nephrol. 2007;2(1):184–191
  22. Lu YP, Zhu YC, Liang MZ, Nan F, Yu Q, Wang L, et al. Therapeutic drug monitoring of mycophenolic acid can be used as predictor of clinical events for kidney transplant recipients treated with mycophenolate mofetil. Transplant Proc. 2006;38(7):2048–2050
  23. Glander P, Hambach P, Braun KP, Fritsche L, Waiser J, Mai I, et al. Effect of mycophenolate mofetil on IMP dehydrogenase after the first dose and after long-term treatment in renal transplant recipients. Int J Clin Pharmacol Ther. 2003;41(10):470–476
  24. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46(1):13–58
  25. Weimert NA, Derotte M, Alloway RR, Woodle ES, Vinks AA. Monitoring of inosine monophosphate dehydrogenase activity as a biomarker for mycophenolic acid effect: potential clinical implications. Ther Drug Monit. 2007;29(2):141–149
  26. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725
  27. Hay EM, Bacon PA, Gordon C, Isenberg DA, Maddison P, Snaith ML, et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med. 1993;86(7):447–458
  28. Yee CS, Isenberg DA, Prabu A, Sokoll K, Teh LS, Rahman A, et al. BILAG-2004 index captures systemic lupus erythematosus disease activity better than SLEDAI-2000. Ann Rheum Dis. 2008;67(6):873–876
  29. Cellcept [Package Insert]. Nutley, NJ, USA: Roche Laboratories, Inc; 2009;
  30. Glander P, Braun KP, Hambach P, Bauer S, Mai I, Roots I, et al. Non-radioactive determination of inosine 5′-monophosphate dehydro-genase (IMPDH) in peripheral mononuclear cells. Clin Biochem. 2001;34(7):543–549
  31. Glander P, Sombogaard F, Budde K, van Gelder T, Hambach P, Liefeldt L, et al. Improved assay for the nonradioactive determination of inosine 5′-monophosphate dehydrogenase activity in peripheral blood mononuclear cells. Ther Drug Monit. 2009;31(3):351–359
  32. Zahr N, Amoura Z, Debord J, Hulot JS, Saint-Marcoux F, Marquet P, et al. Pharmacokinetic study of mycophenolate mofetil in patients with systemic lupus erythematosus and design of Bayesian estimator using limited sampling strategies. Clin Pharmacokinet. 2008;47(4):277–284
  33. Roland M, Barbet C, Paintaud G, Magdelaine-Beuzelin C, Diot E, Halimi JM, et al. Mycophenolate mofetil in patients with systemic lupus erythematosus: a prospective pharmacokinetic study. Lupus. 2009;18(5):441–447
  34. Kuypers DR, de Jonge H, Naesens M, de Loor H, Halewijck E, Dekens M, et al. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients. Clin Ther. 2008;30(4):673–683
  35. Franzblau AN. A primer of statistics for non-statisticians. New York (NY): Harcourt; 1958;
  36. Brunner HI, Higgins GC, Wiers K, Lapidus SK, Olson JC, Onel K, et al. Health-related quality of life and its relationship to patient disease course in childhood-onset systemic lupus erythematosus. J Rheumatol. 2009;36(7):1536–1545
  37. Wais T, Fierz W, Stoll T, Villiger PM. Subclinical disease activity in systemic lupus erythematosus: immunoinflammatory markers do not normalize in clinical remission. J Rheumatol. 2003;30(10):2133–2139
  38. van Hest RM. Population-specific limited sampling strategies for therapeutic drug monitoring of mycophenolic acid. J Postgrad Med. 2006;52(4):244
  39. Armstrong VW, Shipkova M, Schutz E, Weber L, Tonshoff B, Oellerich M. Monitoring of mycophenolic acid in pediatric renal transplant recipients. Transplant Proc. 2001;33(1-2):1040–1043
  40. Zahr N, Hulot J, Haroche J, Debord J, Costedoat-Chalumeau N, Cacoub P, et al. Low mycophenolic acid area under the curve is associated with increased systemic lupus erythematosus activity [Abstract]. Fundam Clin Pharmacol. 2008;22(s1):23
  41. Arnaud L, Zahr N, Haroche J, Hulot J, Marquet P, Funck-Brentano C, et al. Low mycophenolic acid area under the curve Is a major parameter of systemic lupus erythematosus activity [Abstract]. Arthritis Rheum. 2009;60(s1):
  42. Soars MG, Petullo DM, Eckstein JA, Kasper SC, Wrighton SA. An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes. Drug Metab Dispos. 2004;32(1):140–148
  43. Kanou M, Usui T, Ueyama H, Sato H, Ohkubo I, Mizutani T. Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone. Mol Biol Rep. 2004;31(3):151–158
  44. 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(5):321–330
  45. Lam S, Partovi N, Ting LS, Ensom MH. Corticosteroid interactions with cyclosporine, tacrolimus, mycophenolate, and sirolimus: fact or fiction?. Ann Pharmacother. 2008;42(7):1037–1047
  46. Kuypers DR, Claes K, Evenepoel P, Maes B, Coosemans W, Pirenne J, et al. Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients. J Clin Pharmacol. 2003;43(8):866–880
  47. Gregoor PJ, de Sevaux RG, Hene RJ, Hesse CJ, Hilbrands LB, Vos P, et al. Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients. Transplantation. 1999;68(10):1603–1606

 The study is supported by a NIAMS P60-AR047884 grant, the CCHMC Translational Research Initiative, and the Center for Clinical and Translational Research UL1-RR026314. Drs. Vinks and Fukuda are supported by NIH Grant 5U10HD037249. Dr. Vinks is supported by NIH Grant 5K24HD050387. Drs. Wiers and Sherwin are supported by a NIAMS T32 AR007594 grant. Dr. Wiers is supported by the NIH Loan Repayment Program.

PII: S0049-0172(10)00082-X

doi: 10.1016/j.semarthrit.2010.05.007

Seminars in Arthritis and Rheumatism
Volume 40, Issue 4 , Pages 307-313 , February 2011

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