The Journal of Heart and Lung Transplantation
Volume 29, Issue 5 , Pages 509-516 , May 2010

Genetic polymorphisms influence mycophenolate mofetil–related adverse events in pediatric heart transplant patients

  • Erin L. Ohmann, BS

      Affiliations

    • Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Gilbert J. Burckart, PharmD

      Affiliations

    • Office of Clinical Pharmacology, U.S. Food and Drug Administration, Silver Spring, Maryland
    • ,
  • Maria M. Brooks, PhD

      Affiliations

    • Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Yan Chen, MD

      Affiliations

    • Department of Pharmacy, University of Southern California, Los Angeles, California
    • ,
  • Vera Pravica, MD, PhD

      Affiliations

    • Department of Pharmacy, University of Southern California, Los Angeles, California
    • ,
  • Diana M. Girnita, MD

      Affiliations

    • Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Adriana Zeevi, PhD

      Affiliations

    • Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Steven A. Webber, MBChB

      Affiliations

    • Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
    • Corresponding Author InformationReprint requests: Steven A. Webber, MBChB, Division of Cardiology, Children's Hospital of Pittsburgh, 45th Street at Penn Avenue, Pittsburgh, PA 15201. Telephone: 412-692-3216. Fax: 412-692-5138

References 

  1. Boucek MM, Aurora P, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: tenth official pediatric heart transplantation report—2007. J Heart Lung Transplant. 2007;26:796–807
  2. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118
  3. Browne BJ. The Tricontinental Mycophenolate Mofetil Trial. Transplantation. 1996;62:1697
  4. Dipchand AI, Benson L, McCrindle BW, et al. Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience. Pediatr Transplant. 2001;5:112–118
  5. Kobashigawa JA, Meiser BM. Review of major clinical trials with mycophenolate mofetil in cardiac transplantation. Transplantation. 2005;80(suppl):S235–S243
  6. Meur YL, Büchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7:2496–2503
  7. van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86:1043–1051
  8. Hesselink DA, van Gelder T. Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin Pharmacol Ther. 2005;78:317–321
  9. Kuypers DRJ, Naesens M, Vermeire S, et al. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther. 2005;78:351–361
  10. Levesque E, Delage R, Benoit-Biancamano MO, et al. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther. 2007;81:392–400
  11. Kagaya H, Inoue K, Miura M, et al. Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007;63:279–288
  12. Bernard O, Tojcic J, Journault K, et al. Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metabol Dispos. 2006;34:1539–1545
  13. Djebli N, Picard N, Rerolle J-P, et al. 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
  14. Naesens M, Kuypers DRJ, Verbeke K, et al. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation. 2006;82:1074–1084
  15. Sai K, Saito Y, Itoda M, et al. Genetic variations and haplotypes of ABCC2 encoding MRP2 in a Japanese population. Drug Metab Pharmacokin. 2008;23:139–147
  16. Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007;63:1161–1169
  17. Wang J, Yang JW, Zeevi A, et al. IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients. Clin Pharmacol Ther. 2008;83:711–717
  18. Wang JA, Zeevi AC, Webber SC, et al. A novel variant L263F in human inosine 5'-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Pharmacogenet Genom. 2007;17:283–290
  19. Common terminology criteria for adverse events version 3.0 (CTCAE), August 9, 2006. National Cancer Institute; 2006;
  20. Hesselink DA, van Hest RM, Mathot RAA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant. 2005;5:987–994
  21. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation. 1996;61:1029–1037
  22. Eisen HJ, Kobashigawa J, Keogh A, et al. Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant. 2005;24:517–525
  23. Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation. 1998;66:507–515
  24. Keogh A. Long-term benefits of mycophenolate mofetil after heart transplantation. [erratum appears in Transplantation. 2005 Apr 27;79(8):986] Transplantation. 2005;79(suppl):S45–S46
  25. Weimer R, Mytilineos J, Feustel A, et al. Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients. Transplantation. 2003;75:2090–2099
  26. Roth D, Colona J, Burke GW, et al. Primary immunosuppression with tacrolimus and mycophenolate mofetil for renal allograft recipients. Transplantation. 1998;65:248–252
  27. Butani L, Palmer J, Baluarte HJ, et al. Adverse effects of mycophenolate mofetil in pediatric renal transplant recipients with presumed chronic rejection. Transplantation. 1999;68:83–86
  28. Kim JJ, Dreyer WJ, O'Brian Smith E, et al. Leukocyte suppression is associated with improved clinical outcomes in children's status after orthotopic heart transplantation. J Heart Lung Transplant. 2006;25:195–199
  29. van Gelder T, Hilbrands LB, Vanrenterghem Y, 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
  30. Sombogaard F, van Schaik RH, Mathot RA, 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
  31. Weber LT, Shipkova M, Armstrong VW, et al. The pharmacokinetic–pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: a report of the German Study Group on Mycophenolate Mofetil Therapy. J Am Soc Nephrol. 2002;13:759–768
  32. Cattaneo D, Gaspari F, Ferrari S, et al. Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients. Clin Transplant. 2001;15:402–409
  33. Bunnapradist S, Lentine KL, Burroughs TE, et al. Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure. Transplantation. 2006;82:102–107
  34. Galiwango PJ, Delgado DH, Yan R, et al. Mycophenolate mofetil dose reduction for gastrointestinal intolerance is associated with increased rates of rejection in heart transplant patients. J Heart Lung Transplant. 2008;27:72–77
  35. Knoll GA, MacDonald I, Khan A, et al. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol. 2003;14:2381–2386
  36. Gajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: does the MPA level matter?. Am J Transplant. 2004;4:1495–1500
  37. Neerman MF, Boothe DM. A possible mechanism of gastrointestinal toxicity posed by mycophenolic acid [erratum appears in Pharmacol Res. 2003 Oct;48(4):415]. Pharmacol Res. 2003;47:523–526
  38. Westley IS, Brogan LR, Morris RG, et al. Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites: effect of cyclosporine. Drug Metabol Dispos. 2006;34:261–266
  39. Shipkova M, Spielbauer B, Voland A, et al. cDNA microarray analysis reveals new candidate genes possibly linked to side effects under mycophenolate mofetil therapy. Transplantation. 2004;78:1145–1152
  40. Shipkova M, Armstrong VW, Oellerich M, et al. Acyl glucuronide drug metabolites: toxicological and analytical implications. Ther Drug Monit. 2003;25:1–16
  41. Wieland E, Shipkova M, Schellhaas U, et al. Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects?. Clin Biochem. 2000;33:107–113
  42. Grinyo JM, Ekberg H, Mamelok RD, et al. The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony Pharmacokinetic Substudy. Nephrol Dial Transplant. 2009;24:2269–2276
  43. Girnita DM, Brooks MM, Webber SA, et al. Genetic polymorphisms impact the risk of acute rejection in pediatric heart transplantation: a multi-institutional study. Transplantation. 2008;85:1632–1639
  44. Girnita DM, Webber SA, Ferrell R, et al. Disparate distribution of 16 candidate single nucleotide polymorphisms among racial and ethnic groups of pediatric heart transplant patients. Transplantation. 2006;82:1774–1780

PII: S1053-2498(09)01506-X

doi: 10.1016/j.healun.2009.11.602

The Journal of Heart and Lung Transplantation
Volume 29, Issue 5 , Pages 509-516 , May 2010

Article Tools