Immunosuppression in pediatric solid organ transplantation: Opportunities, risks, and management
Anil Dhawan
Paediatric Liver Centre, King's College Hospital and King's College London School of Medicine, London, UK
Search for more papers by this authorAnil Dhawan
Paediatric Liver Centre, King's College Hospital and King's College London School of Medicine, London, UK
Search for more papers by this authorAbstract
Abstract: The pediatric transplant community stands at a time of unprecedented choice of immunosuppressive agents – and with a legacy of morbidity from those agents used in the previous two decades. This review considers the clinical utility and side-effect profiles of immunosuppressants used widely in current practice (e.g., glucocorticoids, azathioprine, ciclosporin, tacrolimus, mycophenolate, and sirolimus) and those agents which are in increasing use or in evaluation (e.g., IL-2 receptor antibodies, everolimus, FTY720, LEA29Y, and deoxyspergualin). Further consideration is given to the wider drug interactions likely during the use of new immunosuppressant regimens and to our growing awareness of the influences of genetic heterogeneity on drug efficacy and handling. Finally, we consider the new demands being placed on the use of drug monitoring to regulate dosage of this new repertoire of immunosuppressants.
References
- 1 Calne R. Cyclosporine as a milestone in immunosuppression. Transplant Proc 2004: 36(Suppl. 2): 13S–15S.
- 2 Habwe VQ. Posttransplantation quality of life: More than graft function. Am J Kidney Dis 2006: 47(Suppl. 2): S98–S110.
- 3 AL-Hussaini A, Tredger JM, Dhawan A. Immunosuppression in pediatric liver and intestinal transplantation: A closer look at the arsenal. J Pediatr Gastroenterol Nutr 2005: 41: 152–165.
- 4 Krieger NR, Emre S. Novel immunosuppressants. Pediatr Transplant 2004: 8: 594–599.
- 5 Dollery C. Therapeutic Drugs, 2nd edn, Vol. 1. Edinburgh: Churchill Livingstone, 1999.
- 6 Dollery C. Therapeutic Drugs, 2nd edn, Vol. 2. Edinburgh: Churchill Livingstone, 1999.
- 7 Allison AC, Eugui EM. Mechanism of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 2005: 80: S181–S190.
- 8 Napoli KL, Taylor PJ. From beach to bedside: History of the development of sirolimus. Ther Drug Monit 2001: 23: 559–586.
- 9 Chapman TM, Perry CM. Everolimus. Drugs 2004: 64: 861–872.
- 10 Kunzendorf U, Ziegler E, Kabelitz D. FTY720 – The first compound of a new promising class of immunosuppressive drugs. Nephrol Dial Transplant 2004: 19: 1677–1681.
- 11 Larsen CP, Knechtle SJ, Adams A, Pearson T, Kirk AD. A new look at blockade of T-cell costimulation: A therapeutic strategy for long-term maintenance immunosuppression. Am J Transplant 2006: 6: 876–883.
- 12 Magee JC, Bucuvalas JC, Farmer DG, Harmon WE, Hulbert-Shearon TE, Mendeloff EN. Pediatric transplantation. Am J Transplant 2004: 4(Suppl. 9): 54–71.
- 13 Mcdiarmid SV, Anand R, Lindblad AS, Group TSR. Studies of pediatric liver transplantation: 2002 update. An overview of demographics, indications, timing and immunosuppressive practices in pediatric liver transplantation in the United States and Canada. Pediatr Transplant 2002: 8: 284–294.
- 14 Smith JM, Nemeth TL, Mcdonald RA. Current immunosuppressive agents in pediatric renal transplantation: Efficacy, side-effects and utilization. Pediatr Transplant 2004: 8: 445–453.
- 15 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: 1054–1061.
- 16 Martin SR, Atkinson P, Anand R, Lindblad AS, Group SR. Studies of pediatric liver transplantation 2002: Patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada. Pediatr Transplant 2004: 8: 273–283.
- 17 Verma A, Wade JJ, Cheeseman P, et al. Risk factors for fungal infection in paediatric liver transplant recipients. Pediatr Transplant 2005: 9: 220–225.
- 18 Haysom L, Rosenberg AR, Kainer G, et al. BK viral infection in an Australian pediatric renal transplant population. Pediatr Transplant 2004: 8: 480–484.
- 19 Dharnidharkva VR, Tejani AH, Ho PL, Harmon WE. Post-transplant lymphproliferative disorder in the United States: Young Caucasian males are at highest risk. Am J Transplant 2002: 2: 993–998.
- 20 Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005: 80: S254–S264.
- 21 Cattaneo D, Gotti E, Perico N, Bertolini G, Kainer G, Remuzzi G. Cyclosporine formulation and Kaposi's sarcoma after renal transplantation. Transplantation 2005: 80: 743–748.
- 22 Adami J, Gäbel H, Lindelöf B, et al. Cancer risk following organ transplantation: A nationwide cohort study in Sweden. Br J Cancer 2003: 89: 1221–1227.
- 23 Benlloch S, Berenguer M, Prieto M, et al. De novo internal neoplasms after liver transplantation: Increased risk and aggressive behaviour in recent years? Am J Transplant 2004: 4: 596–604.
- 24 Carroll RP, Ramsay HM, Fryer AA, Hawley CM, Nicol DL, Harden PN. Incidence and prediction of non-melanoma skin cancer post-renal transplantation: A prospective study in Queensland, Australia. Am J Kidney Dis 2003: 41: 676–683.
- 25 Penn I. De novo malignancy in pediatric organ transplant recipients. J Pediatr Surg 1994: 29: 221–228.
- 26 Shroff R, Rees L. The post-transplant proliferative disorder: A literature review. Pediatr Nephrol 2004: 19: 369–377.
- 27 Allen UD, Farkas G, Hebert D, et al. Risk factors for post-transplant proliferative disorder in pediatric patients: A case control study. Pediatr Transplant 2005: 9: 450–455.
- 28 Lee TC, Savoldo B, Barshes NR, et al. Use of cytokine polymorphisms and Epstein Barr virus viral load to predict development of post-transplant proliferative disorder in paediatric liver transplant recipients. Clin Transplant 2006: 20: 389–393.
- 29 Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, Bustami RT, Dyke DB. Immunosuppression: Practice and trends. Am J Transplant 2004: 4(Suppl. 9): 38–53.
- 30 Filler G, Webb NJA, Milford DV, et al. Four-year data after pediatric renal transplantation: A randomized trial of tacrolimus vs cyclosporin microemulsion. Pediatr Transplant 2005: 9: 498–503.
- 31 Yuan J, Zhou J, Chen BC, et al. Magnesium supplementation prevents chronic cyclosporine nephrotoxicity via adjusting nitric oxide synthase activity. Transplant Proc 2005: 37: 1892–1895.
- 32 Campbell KM, Yazigi N, Ryckman FC, et al. High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation. J Pediatr 2006: 148: 475–480.
- 33 Arora-Gupta N, Davies P, Mckiernan P, Kelly DA. The effect of long-term calcineurin inhibitor therapy on renal function in children after liver transplantation. Pediatr Transplant 2004: 8: 145–150.
- 34 Fine RN. Renal function following liver transplantation in children. Pediatr Transplant 2005: 9: 680–684.
- 35 Alonso EM. Long-term renal function in pediatric liver and heart recipients. Pediatr Transplant 2004: 8: 381–385.
- 36 Ojo AO, Held PJ, Port FK. Chronic renal failure after transplantation of a non-renal organ. N Engl J Med 2003: 349: 931–940.
- 37 Oetjen E, Baun D, Beimesche S, et al. Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin a and tacrolimus in primary, mature islets of transgenic mice. Mol Pharmacol 2003: 63: 1289–1295.
- 38 Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003: 3: 178–185.
- 39 Greenspan LC, Gitelman SE, Leung MA, Glidden DV, Mathias RS. Increased incidence of post-transplant diabetes mellitus in children: A case–control analysis. Pediatr Nephrol 2004: 17: 1–5.
- 40 Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: A systematic review and meta-analysis. Am J Transplant 2004: 4: 583–595.
- 41 AL-Uzri A, Stablein DM, Cohn R. Posttransplant diabetes mellitus in pediatric renal transplant recipients: A report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 2001: 72: 1020–1024.
- 42 Midtvedt K, Hjelmesaeth J, Hartmann A, et al. Insulin resistance after renal transplantation: The effect of steroid dose reduction and withdrawal. J Am Soc Nephrol 2004: 15: 3233–3239.
- 43 Siirtola A, Antikainen M, Ala-Houhala M, et al. Serum lipids in children 3–5 years after kidney, liver and heart transplantation. Transpl Int 2004: 17: 109–119.
- 44 Armstrong AK, Goldberg CS, Crowley DC, Wei W, Gajarski RJ. Effect of age on lipid profiles in pediatric heart transplant recipients. Pediatr Transplant 2005: 9: 523–530.
- 45 Seipelt IM, Crawford SE, Rodgers S, et al. Hypercholesterolemia is common after pediatric heart transplantation: Initial experience with pravastatin. Pediatr Transplant 2005: 23: 317–322.
- 46 Lucey MR, Abdelmalek MF, Gagliardi R, et al. A comparison of tacrolimus and cyclosporine in liver transplantation: Effects on renal function and cardiovascular risk status. Am J Transplant 2005: 5: 1111–1119.
- 47 Mitsnefes MM. Hypertension and end-organ damage in pediatric renal transplantation. Pediatr Transplant 2004: 8: 394–399.
- 48 O'Sullivan JJ, Derrick G, Gray J. Blood pressure after cardiac transplantation in childhood. J Heart Lung Transplant 2005: 24: 891–895.
- 49 Silverstein DM. Risk factors for cardiovascular disease in pediatric renal transplant recipients. Pediatr Transplant 2004: 8: 386–393.
- 50 Saland JM. Osseous complications of pediatric transplantation. Pediatr Transplant 2004: 8: 400–415.
- 51 Ganschow R, Albani J, Grabhorn E, Richter A, Burdelski M. Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection. Pediatr Transplant 2006: 10: 220–224.
- 52 Bucuvalas JC, O CA, Buschle K, et al. Risk of hearing impairment in pediatric liver transplant recipients: A single centre study. Pediatr Transplant 2003: 7: 265–269.
- 53 Deutsch ES, Bartling V, Lawenda B, Schwegler J, Falkenstein KP, Dunn SP. Sensorineural hearing loss in children after liver transplantation. Arch Otolaryngol Head Neck Surg 1998: 124: 529–533.
- 54 Rifai K, Kirchner GI, Bahr MJ, et al. A new side-effect of immunosuppression: High incidence of hearing impairment after liver transplantation. Liver Transplantation 2006: 12: 411–415.
- 55 Ettenger R, Sarwal MM. Mycophenolate mofetil in pediatric renal transplantation. Transplantation 2005: 80: S201–S210.
- 56 Helderman JH, Bennett WM, Cibrik DM, Kaufman DB, Klein A, Takemoto SK. Immunosuppression: practice and trends. Am J Transplant 2003: 3(Suppl. 4): 41–52.
- 57 Armstrong VW, Shipkova M, Van Ahsen N, Oellerich M. Analytic aspects of monitoring therapy with thiopurine medications. Ther Drug Monit 2004: 26: 220–226.
- 58 Zimmerman HJ. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver, 2nd edn. Philadelphia, Lippincott: Williams and Wilkins, 1999: 789.
- 59 Bunchman T, Navarro MT, Brover M, et al. The use of mycophenolate mofetil suspension in pediatric renal allograft recipients. Pediatr Nephrol 2001: 16: 978–984.
- 60 Wiesner R, Rabkin J, Klintmalm G, et al. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transplantation 2001: 7: 442–450.
- 61 Kahan BD. Individuality: The barrier to optimal immunosuppression. Nat Rev Immunol 2003: 3: 831–838.
- 62 Vitco S, Margreiter R, Weimar W, et al. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant recipients. Am J Transplant 2005: 5: 2521–2530.
- 63 Hymes LC, Warshaw BL. Sirolimus in pediatric patients: Results in the first 6 months post-renal transplant. Pediatr Transplant 2005: 9: 520–522.
- 64 Jimenez-Rivera C, Avitzur Y, Fecteau AH, Jones N, Grant D, NG VL. Sirolimus for pediatric liver transplant recipients with post-transplant lymphoproliferative disease and hepatoblastoma. Pediatr Transplant 2004: 8: 243–248.
- 65 Lobach NE, Pollock-Barziv SM, West LJ, Dipchand AI. Sirolimus immunosuppression in pediatric heart transplant recipients: A single centre experience. J Heart Lung Transplant 2005: 24: 184–189.
- 66 Montalbano M, Neff GW, Yamashiki N, et al. A retrospective review of liver transplant patients treated with sirolimus from a single centre: An analysis of sirolimus-related complications. Transplantation 2004: 78: 264–268.
- 67 Hoyer PF, Ettenger R, Kovarik JM, et al. Everolimus in pediatric de novo renal transplant patients. Transplantation 2003: 75: 2082–2085.
- 68 Vester U, Kranz B, Wehr S, Boger R, Hoyer PF, Group ARBS. Everolimus (Certican) in combination with Neoral in pediatric renal transplant recipients: Interim analysis after 3 months. Transplant Proc 2002: 34: 2209–2210.
- 69 Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: A 3-year, randomized, multicenter, phase III study. Transplantation 2005: 80: 244–252.
- 70 Morelon E, Kreis H. Sirolimus therapy without calcineurin inhibitors: Necker hospital 8-year experience. Transplant Proc 2003: 35(Suppl.): 52S–57S.
- 71 Ambudkar SV, Day S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999: 39: 361–398.
- 72 Lewis JD, Bachmann KA. Cytochrome P450 enzymes and drug-drug interactions: An update on the superfamily. J Pharm Technol 2006: 22: 22–31.
- 73 Westphal K, Weinbrenner A, Zschiesche M, et al. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction. Clin Pharmacol Ther 2000: 68: 345–355.
- 74 Tredger JM, Brown NW. Mycophenolate: Better value through monitoring? Transplantation 2006: 81: 507–508.
- 75 Van Gelder T, Shaw LM. The rationale for and limitations of therapeutic drug monitoring for mycophenolate mofetil in transplantation. Transplantation 2005: 80(Suppl. 2): S244–S253.
- 76 Ferraris JR, Duca P, Prigoshin N, et al. Mycophenolate mofetil and reduced doses of cyclosporine in pediatric liver transplantation with chronic renal dysfunction: Changes in the immune response. Pediatr Transplant 2004: 8: 454–459.
- 77 AW MM, Brown N, Itsuka T, et al. Mycophenolic acid pharmacokinetics in pediatric liver transplant recipients. Liver Transplantation 2003: 9: 383–388.
- 78 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: 687–994.
- 79 Brown N, AW MM, Mieli-Vergani G, Dhawan A, Tredger JM. Mycophenolic acid and mycophenolic acid glucuronide pharmacokinetics in pediatric liver transplant recipients: Effect of cyclosporine and tacrolimus comedication. Ther Drug Monit 2002: 24: 598–606.
- 80 Ettenger R, Bartosh S, Choi L, et al. Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients. Pediatr Transplant 2005: 9: 780–787.
- 81 Kuypers DRJ, Naesens M, Vermiere S, Vanrenterghem Y. The impact of uridine diphosphate glucuronyltransferase 1A9 (UGT1A9) gene promoter region single nucleotide polymorphism T-275A and C2152T on early mycophenolic acid dose interval exposure in de novo renal allograft recipients. Clin Pharamcol Ther 2005: 78: 351–361.
- 82 Shaw LM, Holt DW, Oellerich M, Meiser B, Van Gelder T. Current issues in therapeutic drug monitoring of mycophenolic acid: Report of a roundtable discussion. Ther Drug Monit 2001: 23: 305–315.
- 83 Cattaneo D, Gaspari F, Gotti E, Remuzzi G, Perico N. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int 2002: 62: 1060–1067.
- 84 Filler G, Gellermann J, Zimmering M, Mai I. Effect of adding mycophenolate mofetil in pediatric renal recipients with cyclosporin nephrotoxicity. Transpl Int 2000: 13: 201–206.
- 85 Hocker B, John U, Plank C, et al. Successful withdrawal of steroids in pediatric renal transplant recipients receiving cyclosporine A and mycophenolate mofetil treatment: Results after four years. Transplantation 2004: 78: 228–234.
- 86 Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Milan M, Salvatierra O. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation 2003: 76: 1331–1339.
- 87 Appel G, Radhakrishnan J, Ginzler EM. Use of mycophenolate mofetil in autoimmune and renal diseases. Transplantation 2005: 80: S265–S271.
- 88 Pape L, Froede K, Srehlau J, Ehrich JHH, Offner G. Alterations of cyclosporin A metabolism induced by mycophenolate mofetil. Pediatr Transplant 2003: 7: 302–304.
- 89 Buck ML. Immunosuppression with sirolimus after solid organ transplantation in children. Pediatric Pharmacother 2006: 12: 1–5.
- 90 Gupta P, Kaufman S, Fishbein TM. Sirolimus for solid organ transplantation in children. Pediatr Transplant 2005: 9: 269–276.
- 91 Schachter AD, Meyers KE, Spaneas LD, et al. Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 2004: 8: 171–177.
- 92 Casas-Melley AT, Falkenstein KP, Flynn LM, Ziegler VL, Dunn SP. Improvement in renal function and rejection control in pediatric liver transplant recipients with the introduction of sirolimus. Pediatr Transplant 2004: 8: 362–366.
- 93 Lampen A, Zhang Y, Hackbarth I, Benet LZ, Sewing K-F, Christians U. Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. J Pharmacol Exp Ther 1998: 285: 1104–1112.
- 94 Cattaneo D, Merlini S, Perico N, et al. Therapeutic drug monitoring of sirolimus; effect of concommitant immunosuppressive therapy and clinical management. Am J Transplant 2004: 4: 1345–1351.
- 95 Sindhi R, Webber S, Venkataramanan R, et al. Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus. Transplantation 2001: 72: 851–855.
- 96 Watson CJE. Sirolimus (rapamycin) in clinical transplantation. Transplant Rev 2001: 15: 165–177.
- 97 Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal transplant recipients. N Engl J Med 2005: 352: 1317–1323.
- 98 Kahan B, Knight R, Schoenberg L, et al. Ten years of sirolimus therapy for human renal transplantation: The University of Texas at Houston experience. Transplant Proc 2003: 35: 25S–34S.
- 99 Muthukkumar S, Ramesh TM, Bondada S. Rapamycin, a potent immunosuppessive drug causes programmed cell death in B lymphoma cells. Transplantation 1995: 60: 264–270.
- 100 Burton CM, Andersen CB, Jensen AS, et al. The incidence of acute cellular rejection after lung transplantation: A comparative study of anti-thymocyte globulin and daclizumab. J Heart Lung Transplant 2006: 25: 638–647.
- 101
Botha JF,
Horslen SP.
Small bowel transplantation: Literature review.
Pediatr Transplant
2006: 10: 7–16.
10.1111/j.1399-3046.2005.00407.x Google Scholar
- 102 Wilmot I, Kanter KR, Vincent RN, Berg AM, Mahle WT. OKT3 treatment in refractory pediatric heart transplant rejection. J Heart Lung Transplant 2005: 24: 1793–1797.
- 103 Bartosh SM, Knechtle SJ, Sollinger HW. Campath-1H use in pediatric renal transplantation. Am J Transplant 2005: 5: 1569–1573.
- 104 Loinaz C, Mirttal N, Kato T, Miller BW, Rodriguez M, Tzakis A. Multivisceral transplantation for pediatric intestinal pseudo-obstruction: Single centre's experience of 16 cases. Transplant Proc 2004: 36: 312–313.
- 105 Chin C, Pittson S, Luikart H, et al. Induction therapy for pediatric and adult heart transplantation: Comparison between OKT3 and daclizumab. Transplantation 2005: 80: 477–481.
- 106 De Filippo S. Anti-IL-2 receptor antibody vs. polyclonal anti-lymphocyte antibody as induction therapy in pediatric transplantation. Pediatr Transplant 2005: 9: 373–380.
- 107 Heffron TG, Pillen T, Smallwood GA, Welch D, Oakley B, Romero R. Pediatric liver transplantation with daclizumab induction. Transplantation 2003: 75: 2040–2043.
- 108 Farmer DG, Mcdiarmid SV, Edelstein JF, et al. Induction therapy with interleukin-2 receptor anatagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function. Transplant Proc 2004: 36: 331–332.
- 109 Sweet SC, Dela Morena MT, Shapiro SD, Mendeloff EN, Huddleston CB. Interleukin-2 receptor blockade with daclizumab decreases the incidence of acute rejection in pediatric lung transplantation (abstract). J Heart Lung Transplant 2001: 20: 221.
- 110 Tejani A, Ping-Leung H, Emmett L, Stablein DM. Reduction in acute rejections decreases chronic rejection graft failure in children: A report of the North American Pediatric renal transplant Cooperative Study. Am J Transplant 2002: 2: 142–147.
- 111 Nelson DR, Soldevila-Pico C, Reed A, et al. Anti-Interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation. Liver Transplantation 2001: 7: 1064–1070.
- 112 Strehlau J, Pape L, Offner G, Nashan B, Ehrich JHH. Interleukine-2 receptor antibody-induced alterations of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000: 356: 1327–1328.
- 113 Vincenti F, Larsen CP, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl JMed 2005: 353: 770–781.
- 114 Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA-4Ig with potent immunosuppressive properties. Am J Transplant 2005: 5: 443–453.
- 115 Lorber MI, Poticelli C, Whelchel J, Mayer HW, LI Y, Schmidli H. Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy and safety data. Clin Transplant 2005: 19: 145–152.
- 116 Kovarik JM, Tedesco H, Pascual J, et al. Everolimus therapeutic concentration range defined from a prospective trial with reduced exposure cyclosporine in de novo kidney transplantation. Ther Drug Monit 2004: 26: 499–505.
- 117 Chapman JR, O'Connell PJ, Bovington KJ, Allen RD. Reversal of cyclosporine malabsorption in diabetic recipients of simultaneous pancreas and kidney transplant using microemulsion formulation. Transplantation 1996: 61: 1699–1704.
- 118 Kovarik JM, Dantal J, Civati G, et al. Influence of delayed initiation of cyclosporine on everolimus pharmacokinetics in de novo renal transplant patients. Am J Transplant 2003: 3: 1576–1580.
- 119 Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005: 80: 883–889.
- 120 Ferguson RM, Mulgaonkar S, Tedesco H, Al E. High efficacy of FTY720 with reduced cyclosporine dose in preventing rejection in renal transplantation: 12-month preliminary results. Am J Transplant 2003: 3: 311. (abstract).
- 121 Kovarik JM, Schmouder RL, Slade AL. Overview of FTY720 clinical pharmacokinetics and pharmacology. Ther Drug Monit 2004: 26: 585–587.
- 122 Vanrenterghem Y, Van Hooff JP, Klinger M, et al. The Effects of FK778 in combination with tacrolimus and steroids: A phase II multicenter study in renal transplant patients. Transplantation 2004: 78: 9–14.
- 123 Amemiya H. Deoxyspergualin: Clinical trials in renal graft rejection. Ann N Y Acad Sci 1993: 685: 196–201.
- 124
Kawagishi N,
Satoh K,
Enomoto Y,
Akamatsu Y,
Sekiguchi S,
Satomi S.
Use of deoxyspergualin on steroid-resistant acute rejection in living donor liver transplantation.
Tohoku J Exp Med
2006: 208: 225–233.
10.1620/tjem.208.225 Google Scholar
- 125 Nohima M, Yoshimoto T, Nakao A, et al. Combined therapy of deoxyspergualin and plasmapheresis: A useful treatment for antibody-mediated acute rejection after kidney transplantation. Transplant Proc 2005: 37: 930–933.
- 126 Maezono S, Sugimoto K-I, Sakamoto K-I, et al. Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: Involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein. Pediatr Transplant 2005: 9: 315–323.
- 127 Kim JS, Aviles DH, Silverstein DM, Lb PL, Vehaskari VM. Effect of age, ethnicity and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients. Pediatr Transplant 2005: 9: 162–169.
- 128 Kung L, Batiuk TD, Palomo-Pinon S, Noujaim J, Helms LMH, Halloran PF. Tissue distribution of calcineurin and its sensitivity to inhibition by cyclosporine. Am J Transplant 2001: 1: 325–333.
- 129 Martinez-Martinez S, Redondo JM. Inhibitors of the calcineurin/NFAT pathway. Curr Med Chem 2004: 11: 997–1007.
- 130 Evans EE, Mcleod HL. Pharmacogenomics – Drug disposition, drug targets and side effects. N Engl J Med 2003: 348: 538–549.
- 131 Anglicheau D, Legendre C, Thervet E. Pharmacogenetics in solid organ transplantation: Present knowledge and future perspectives. Transplantation 2004: 78: 311–315.
- 132 Macphee IAM, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 2004: 4: 914–919.
- 133 Rumbo C. Azathioprine metabolite measurements: Its use in current clinical practice. Pediatr Transplant 2004: 8: 606–608.
- 134 Borrows R, Chusney G, Loucaidou M, et al. Mycophenolic ACID 12-h trough level monitoring in renal transplantation: Association with acute rejection and toxicity. Am J Transplant 2006: 6: 121–128.
- 135 Oellerich M, Shipkova M, Schütz E, et al. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: Implications for therapeutic drug monitoring. Ther Drug Monit 2000: 22: 20–26.
- 136 Tredger JM, Brown NW, Adams JE, et al. Monitoring mycophenolate in liver transplant recipients: Towards a therapeutic range. Liver Transplantation 2004: 10: 492–502.
- 137
Holt DW,
Johnston A.
Monitoring immunosuppressive drugs: Has it a future?
Ther Drug Monit
2004: 26: 244–247.
10.1097/00007691-200406000-00003 Google Scholar
- 138 Brown NW, Gonde CE, Adams JE, Tredger JM. Low hematocrit and serum albumin concentrations underlie the overestimation of tacrolimus concentrations by microparticle enzyme immunoassay versus liquid chromatography-tandem mass spectrometry. Clin Chem 2005: 51: 586–592.
- 139 Halloran PF, Helms LMH, Kung L, Noujaim J. The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999: 68: 1356–1361.
- 140 Vethe NT, Mandla R, Line P-D, Midtvedt K, Hartmann A, Bergan S. Inosine monophosphate dehydrogenase activity in renal allograft recipients during mycophenolate treatment. Scand J Clin Lab Invest 2006: 66: 31–44.
- 141 Jorga A, Holt DW, Johnston A. Therapeutic drug monitoring of cyclosporine. Transplant Proc 2004: 36(Suppl. 2S): 396S–403S.
- 142 Filler G, Feber J, Lepage N, Weiler G, Mai I. Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children. Pediatr Transplant 2002: 6: 411–418.
- 143 Cox VC, Ensom MHH. Mycophenolate mofetil for solid organ transplantation: Does the evidence support the need for clinical pharmacokinetic monitoring? Ther Drug Monit 2003: 25: 137–157.
- 144 Macphee IAM, Fredericks S, Tai T, et al. Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome P4503A5 and p-glycoprotein correlate with dose requirement. Transplantation 2002: 74: 1486–1489.
- 145 Thervet E, Anglichaeu D, King B, et al. Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003: 76: 1233–1235.
- 146 Cattaneo D, Perico N, Remuzzi G. From pharmacokinetics to pharmacogenomics: A new approach to tailor immunosuppressive therapy. Am J Transplant 2004: 4: 299–310.
- 147 Schroppel B, Murphy B. Gene variants affecting bioavailability of drugs: Towards individualized immunosuppressive therapy? J Am Soc Nephrol 2003: 14: 1955–1957.