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Pediatric Drugs

, Volume 9, Issue 3, pp 165–174 | Cite as

Calcineurin Inhibitors in Pediatric Renal Transplant Recipients

  • Guido FillerEmail author
Review Article

Abstract

The calcineurin inhibitors, cyclosporine (ciclosporin) [microemulsion] and tacrolimus, are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. For pediatric patients, both drugs should be dosed per body surface area, and pharmacokinetic monitoring is mandatory. While monitoring of the trough levels may suffice for tacrolimus, cyclosporine therapy that utilizes the microemulsion formulation requires additional monitoring (e.g. determination of 2-hour post-dose levels).

In a well designed randomized study in children, as in studies in adults, there was no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However, tacrolimus was significantly more effective than cyclosporine microemulsion in preventing acute rejection after renal transplantation when used in conjunction with azathioprine and corticosteroids. With regard to long-term outcome, the difference in acute rejection episodes resulted in a better glomerular filtration rate at 1 year after transplantation and eventually in better graft survival 4 years after renal transplantation. Whether this difference persists when calcineurin inhibitors are used in combination with mycophenolate mofetil has not been determined. The prevalence of hypomagnesemia was higher in the tacrolimus group whereas hypertrichosis and gingival hyperplasia occurred more frequently in the cyclosporine group. In contrast with adults, the incidence of post-transplantation diabetes mellitus was not significantly different between tacrolimus- and cyclosporine-treated patients. There was also no difference with regard to post-transplantation lymphoproliferative disorder. Medication costs were similar, but in view of the lower rejection episodes and better long-term graft survival as well as the more favorable cosmetic side effect profile, tacrolimus may be preferable.

The recommendation drawn from the available data is that both cyclosporine and tacrolimus can be used safely and effectively in children. We recommend that cyclosporine should be chosen when patients experience tacrolimus-related adverse events.

Keywords

Tacrolimus Graft Survival Mycophenolate Mofetil Calcineurin Inhibitor Acute Rejection Episode 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

No special funding was available for the preparation of this review. However, the author has previously received grant support from both manufacturers of the two available calcineurin inhibitors (Novartis Inc., Basel, Switzerland [cyclosporine microemulsion; Neoral®] and Fujisawa GmbH, Munich, Germany [tacrolimus; Prograf®]).

References

  1. 1.
    Smith JM, Nemeth TL, McDonald RA. Current immunosuppressive agents: efficacy, side effects, and utilization. Pediatr Clin North Am 2003; 50: 1283–300PubMedCrossRefGoogle Scholar
  2. 2.
    Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant 2004; 4: 384–9PubMedCrossRefGoogle Scholar
  3. 3.
    Kari JA, Trompeter RS. What is the calcineurin inhibitor of choice for pediatric renal transplantation? Pediatr Transplant 2004; 8: 437–44PubMedCrossRefGoogle Scholar
  4. 4.
    Calne R. Cyclosporine as a milestone in immunosuppression. Transplant Proc 2004; 36 (2 Suppl.): 13–15SCrossRefGoogle Scholar
  5. 5.
    Dunn CJ, Wagstaff AJ, Perry CM, et al. Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral) in organ transplantation. Drugs 2001; 61: 1957–2016PubMedCrossRefGoogle Scholar
  6. 6.
    Faulds D, Goa KL, Benfield P. Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993; 45: 953–1040PubMedCrossRefGoogle Scholar
  7. 7.
    Peters DH, Fitton A, Plosker GL, et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746–94PubMedCrossRefGoogle Scholar
  8. 8.
    Scott LJ, McKeage K, Keam SJ, et al. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63: 1247–97PubMedCrossRefGoogle Scholar
  9. 9.
    Spencer CM, Goa KL, Gillis JC. Tacrolimus: an update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 1997; 54: 925–75PubMedCrossRefGoogle Scholar
  10. 10.
    Hoppu K, Koskimies O, Holmberg C, et al. Pharmacokinetically determined cyclosporine dosage in young children. Pediatr Nephrol 1991; 5: 1–4PubMedCrossRefGoogle Scholar
  11. 11.
    Jacqz-Aigrain E, Montes C, Brun P, et al. Cyclosporine pharmacokinetics in nephrotic and kidney-transplanted children. Eur J Clin Pharmacol 1994; 47: 61–5PubMedGoogle Scholar
  12. 12.
    Bokenkamp A, Offner G, Hoyer PF, et al. Improved absorption of cyclosporin A from a new microemulsion formulation: implications for dosage and monitoring. Nephrol 1995; 9: 196–8Google Scholar
  13. 13.
    Filler G, Ehrich J. Which cyclosporin formulation? Lancet 1996; 348: 1176–7PubMedCrossRefGoogle Scholar
  14. 14.
    Cooney GF, Habucky K, Hoppu K. Cyclosporin pharmacokinetics in paediatric transplant recipients. Clin Pharmacokinet 1997; 32: 481–95PubMedCrossRefGoogle Scholar
  15. 15.
    Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157–67PubMedCrossRefGoogle Scholar
  16. 16.
    Dunn SP, Cooney GF, Kulinsky A, et al. Absorption characteristics of a microemulsion formulation of cyclosporine in de novo pediatric liver transplant recipients. Transplantation 1995; 60: 1438–42PubMedCrossRefGoogle Scholar
  17. 17.
    Yee GC, Lennon TP, Gmur DJ, et al. Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients. Clin Pharmacol Ther 1986 Oct; 40(4): 438–43PubMedCrossRefGoogle Scholar
  18. 18.
    Filler G, Trompeter R, Webb NJ, et al. One-year glomerular filtration rate predicts graft survival in pediatric renal recipients: a randomized trial of tacrolimus vs cyclosporine microemulsion. Transplant Proc 2002; 34: 1935–8PubMedCrossRefGoogle Scholar
  19. 19.
    Filler G, Mai I, Filler S, et al. Abbreviated cyclosporine AUCs on Neoral: the search continues! Pediatr Nephrol 1999; 13: 98–102PubMedCrossRefGoogle Scholar
  20. 20.
    Primmett DR, Levine M, Kovarik JM, et al. Cyclosporine monitoring in patients with renal transplants: two- or three-point methods that estimate area under the curve are superior to trough levels in predicting drug exposure. Ther Drug Monit 1998; 20: 276–83PubMedCrossRefGoogle Scholar
  21. 21.
    Filler G, Feber J. The transplanted child: new immunosuppressive agents and the need for pharmacokinetics monitoring. Paediatr Child Health 2002; 7: 525–32PubMedGoogle Scholar
  22. 22.
    Dello Strologo L, Pontesilli C, Rizzoni G, et al. C2 monitoring: a reliable tool in pediatric renal transplant recipients. Transplantation 2003; 76: 444–5CrossRefGoogle Scholar
  23. 23.
    Ferraresso M, Ghio L, Zacchello G, et al. Pharmacokinetic of cyclosporine microemulsion in pediatric kidney recipients receiving a quadruple immunosuppressive regimen: the value of C2 blood levels. Transplantation 2005; 79: 1164–8PubMedCrossRefGoogle Scholar
  24. 24.
    Pape L, Ehrich JH, Offner G. Advantages of cyclosporin A using 2-h levels in pediatric kidney transplantation. Pediatr Nephrol 2004; 19: 1035–8PubMedCrossRefGoogle Scholar
  25. 25.
    Trompeter R, Fitzpatrick M, Hutchinson C, et al. Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption. Pediatr Transplant 2003; 7: 282–8PubMedCrossRefGoogle Scholar
  26. 26.
    Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 2001; 40: 283–95PubMedCrossRefGoogle Scholar
  27. 27.
    Webster A, Woodroffe RC, Taylor RS, et al. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005; (4): CD003961Google Scholar
  28. 28.
    Christians U, Strom T, Zhang YL, et al. Active drug transport of immunosuppressants: new insights for pharmacokinetics and pharmacodynamics. Ther Drug Monit 2006; 28: 39–44PubMedCrossRefGoogle Scholar
  29. 29.
    Astellas Pharma US Inc. Prograf prescribing information (US) [online]. Available from URL: http://www.astellas.us/docs/prograf.pdf [Accessed 2006 Apr 29]
  30. 30.
    Montini G, Ujka F, Varagnolo C, et al. The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients. Pediatr Nephrol 2006; 21: 719–24PubMedCrossRefGoogle Scholar
  31. 31.
    Filler G, Grygas R, Mai I, et al. Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants. Nephrol Dial Transplant 1997; 12: 1668–71PubMedCrossRefGoogle Scholar
  32. 32.
    Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005; 331: 810–22PubMedCrossRefGoogle Scholar
  33. 33.
    Trompeter R, Filler G, Webb NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002; 17: 141–9PubMedCrossRefGoogle Scholar
  34. 34.
    Filler G, Webb NJ, Milford DV, et al. Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 2005; 9: 498–503PubMedCrossRefGoogle Scholar
  35. 35.
    Filler G, Browne R, Seikaly MG. Glomerular filtration rate as a putative ‘surrogate end-point’ for renal transplant clinical trials in children. Pediatr Transplant 2003; 7: 18–24PubMedCrossRefGoogle Scholar
  36. 36.
    Cosio FG, Pesavento TE, Osei K, et al. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001; 59: 732–7PubMedCrossRefGoogle Scholar
  37. 37.
    Cosio FG, Pesavento TE, Kim S, et al. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002; 62: 1440–6PubMedCrossRefGoogle Scholar
  38. 38.
    Kasiske BL, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178–85PubMedCrossRefGoogle Scholar
  39. 39.
    Webster A, Woodroffe RC, Taylor RS, et al. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005; (4): CD003961Google Scholar
  40. 40.
    Al-Uzri A, Stablein DM, Cohn AR. Posttransplant diabetes mellitus in pediatric renal transplant recipients: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001; 72: 1020–4PubMedCrossRefGoogle Scholar
  41. 41.
    Tanabe K. Calcineurin inhibitors in renal transplantation: what is the best option? Drugs 2003; 63: 1535–48PubMedCrossRefGoogle Scholar
  42. 42.
    Heisel O, Heisel R, Balshaw R, et al. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004; 4: 583–95PubMedCrossRefGoogle Scholar
  43. 43.
    Weir MR, Fink JC. Risk for posttransplant diabetes mellitus with current immunosuppressive medications. Am J Kidney Dis 1999; 34: 1–13PubMedCrossRefGoogle Scholar
  44. 44.
    Hirano Y, Fujihira S, Ohara K, et al. Morphological and functional changes of islets of Langerhans in FK506-treated rats. Transplantation 1992; 53: 889–94PubMedCrossRefGoogle Scholar
  45. 45.
    Filler G, Neuschulz I, Vollmer I, et al. Tacrolimus reversibly reduces insulin secretion in paediatric renal transplant recipients. Nephrol Dial Transplant 2000; 15: 867–71PubMedCrossRefGoogle Scholar
  46. 46.
    Shroff R, Rees L. The post-transplant lymphoproliferative disorder: a literature review. Pediatr Nephrol 2004; 19: 369–77PubMedCrossRefGoogle Scholar
  47. 47.
    Dharnidharka VR, Sullivan EK, Stablein DM, et al. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001; 71: 1065–8PubMedCrossRefGoogle Scholar
  48. 48.
    Siirtola A, Antikainen M, Ala-Houhala M, et al. Serum lipids in children 3 to 5 years after kidney, liver, and heart transplantation. Transpl Int 2004; 17: 109–19PubMedCrossRefGoogle Scholar
  49. 49.
    Groothoff JW. Long-term outcomes of children with end-stage renal disease. Pediatr Nephrol 2005; 20: 849–53PubMedCrossRefGoogle Scholar
  50. 50.
    Butani L. Prospective monitoring of lipid profiles in children receiving pravastatin preemptively after renal transplantation. Pediatr Transplant 2005; 9: 746–53PubMedCrossRefGoogle Scholar
  51. 51.
    Mitsnefes MM. Hypertension and end-organ damage in pediatric renal transplantation. Pediatr Transplant 2004; 8: 394–9PubMedCrossRefGoogle Scholar
  52. 52.
    Kelly D, Jara P, Rodeck B, et al. Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial. Lancet 2004; 364: 1054–61PubMedCrossRefGoogle Scholar
  53. 53.
    Hardinger KL, Bohl DL, Schnitzler MA, et al. A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients. Transplantation 2005; 80: 41–6PubMedCrossRefGoogle Scholar
  54. 54.
    Lazzaro C, McKechnie T, McKenna M. Tacrolimus versus cyclosporin in renal transplantation in Italy: cost-minimisation and cost-effectiveness analyses. J Nephrol 2002; 15: 580–8PubMedGoogle Scholar
  55. 55.
    Orme ME, Jurewicz WA, Kumar N, et al. The cost effectiveness of tacrolimus versus microemulsified cyclosporin: a 10-year model of renal transplantation outcomes. Pharmacoeconomics 2003; 21: 1263–76PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Department of PediatricsChildren’s Hospital of Eastern OntarioOttawaCanada
  2. 2.Department of PaediatricsSchulich School of Medicine and DentistryLondonCanada

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