Download PDF
Dialyse aktuell 2020; 24(08): 320-326
DOI: 10.1055/a-1176-6466
Schwerpunkt
Transplantation
© Georg Thieme Verlag Stuttgart · New York

Monitoring der immunsuppressiven Therapie

Was sind die Grundlagen und worauf ist bei Nierentransplantation zu achten?
Rasmus Ehren
1   Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät und Uniklinik Köln, Universität zu Köln, Köln
,
Lutz T. Weber
1   Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät und Uniklinik Köln, Universität zu Köln, Köln
› Author Affiliations
Further Information

Publication History

Publication Date:
12 October 2020 (online)

Also available at
    Permissions and Reprints

ZUSAMMENFASSUNG

Das therapeutische Drug-Monitoring (TDM) einer immunsuppressiven Therapie kann einen wichtigen Beitrag zur klinischen Einschätzung des Verlaufes und zur Effektivität der Behandlung leisten. Ziel des TDMs sollte die Optimierung der Medikamentendosierung sein, um eine gute Effektivität bei minimaler Toxizität zu erreichen. Ein TDM kann pharmakokinetisch, pharmakodynamisch und pharmakogenetisch erfolgen. Näher wird auf die Besonderheiten des TDMs von Mycophenolatmofetil (MMF) und Tacrolimus eingegangen. Des Weiteren werden Grundprinzipien und Einflussfaktoren eines TDMs erläutert.

 

  • Literatur

  • 1 Rissling O, Glander P, Hambach P. et al No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study. Br J Clin Pharmacol 2015; 80: 1086-1096 doi:10.1111/bcp.12664
    CrossrefPubMedGoogle Scholar
  • 2 van Boekel GAJ, Kerkhofs CHH, van de Logt F, Hilbrands LB. Proton pump inhibitors do not increase the risk of acute rejection. Neth J Med 2014; 72: 86-90
    PubMedGoogle Scholar
  • 3 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: 1157-1167 doi:10.1056/NEJMra035092
    CrossrefPubMedGoogle Scholar
  • 4 Soldin OP, Soldin SJ. Review: therapeutic drug monitoring in pediatrics. Ther Drug Monit 2002; 24: 1-8 doi:10.1097/00007691-200202000-00001
    CrossrefPubMedGoogle Scholar
  • 5 Kiang TKL, Ensom MHH. Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update. Expert Opin Drug Metab Toxicol 2016; 12: 545-553 doi:10.1517/17425255.2016.1170806
    CrossrefPubMedGoogle Scholar
  • 6 Metz DK, Holford N, Kausman JY. et al Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention. Transplantation 2019; 103: 2012-2030 doi:10.1097/TP.0000000000002762
    CrossrefPubMedGoogle Scholar
  • 7 Andrews LM, Li Y, De Winter BCM. et al Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients. Expert Opin Drug Metab Toxicol 2017; 13: 1225-1236 doi:10.1080/17425255.2017.1395413
    CrossrefPubMedGoogle Scholar
  • 8 Bremer S, Vethe NT, Skauby M. et al NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation. Br J Clin Pharmacol 2017; 83: 2494-2502 doi:10.1111/bcp.13367
    CrossrefPubMedGoogle Scholar
  • 9 Keller F, Sommerer C, Giese T. et al Correlation between pharmacokinetics of tacrolimus and pharmacodynamics on NFAT-regulated gene expression in stable kidney transplant recipients. Clin Nephrol 2017; 87: 93-99 doi:10.5414/CN108893
    CrossrefPubMedGoogle Scholar
  • 10 Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 2005; 5: 472-484 doi:10.1038/nri1632
    CrossrefPubMedGoogle Scholar
  • 11 Glander P, Budde K. Target enzyme activity as a biomarker for immunosuppression. Ther Drug Monit 2010; 32: 257-260 doi:10.1097/FTD.0b013e3181ddd7b3
    CrossrefPubMedGoogle Scholar
  • 12 Rother A, Glander P, Vitt E. et al Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid. Eur J Clin Pharmacol 2012; 68: 913-922 doi:10.1007/s00228-011-1203-4
    CrossrefPubMedGoogle Scholar
  • 13 Sombogaard F, van Schaik RHN, Mathot RA. et al Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757 T > C polymorphism. Pharmacogenet Genomics 2009; 19: 626-634 doi:10.1097/FPC.0b013e32832f5f1b
    CrossrefPubMedGoogle Scholar
  • 14 Weißbarth G, Wiesen MHJ, Fietz C. et al Pharmacodynamic Monitoring of Mycophenolic Acid Therapy: Improved Liquid Chromatography-Tandem Mass Spectrometry Method for Measuring Inosin-5’-Monophosphate Dehydrogenase Activity. Ther Drug Monit 2020; 42: 282-288 doi:10.1097/FTD.0000000000000688
    CrossrefPubMedGoogle Scholar
  • 15 Sommerer C, Giese T. Nuclear Factor of Activated T Cells-Regulated Gene Expression as Predictive Biomarker of Personal Response to Calcineurin Inhibitors. Ther Drug Monit 2016; 38 (Suppl. 01) S50-S56 doi:10.1097/FTD.0000000000000234
    CrossrefPubMedGoogle Scholar
  • 16 Sommerer C, Schaier M, Morath C. et al The Calcineurin Inhibitor-Sparing (CIS) Trial – individualised calcineurin-inhibitor treatment by immunomonitoring in renal allograft recipients: protocol for a randomised controlled trial. Trials 2014; 15: 489 doi:10.1186/1745-6215-15-489
    CrossrefPubMedGoogle Scholar
  • 17 Asadov C, Aliyeva G, Mustafayeva K. Thiopurine S-Methyltransferase as a Pharmacogenetic Biomarker: Significance of Testing and Review of Major Methods. Cardiovasc Hematol Agents Med Chem 2017; 15: 23-30 doi:10.2174/1871525715666170529091921
    CrossrefPubMedGoogle Scholar
  • 18 de Jonge H, de Loor H, Verbeke K. et al In vivo CYP3A4 activity, CYP3A5 genotype, and hematocrit predict tacrolimus dose requirements and clearance in renal transplant patients. Clin Pharmacol Ther 2012; 92: 366-375 doi:10.1038/clpt.2012.109
    CrossrefPubMedGoogle Scholar
  • 19 Shipkova M, Hesselink DA, Holt DW. et al Therapeutic Drug Monitoring of Everolimus: A Consensus Report. Ther Drug Monit 2016; 38: 143-169 doi:10.1097/FTD.0000000000000260
    CrossrefPubMedGoogle Scholar
  • 20 Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995; 17: 681-684 doi:10.1097/00007691-199512000-00023
    CrossrefPubMedGoogle Scholar
  • 21 Bunchman T, Navarro M, Broyer M. et al The use of mycophenolate mofetil suspension in pediatric renal allograft recipients. Pediatr Nephrol 2001; 16: 978-984 doi:10.1007/s004670100006
    CrossrefPubMedGoogle Scholar
  • 22 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 doi:10.1097/00007890-199907270-00018
    CrossrefPubMedGoogle Scholar
  • 23 Kuypers DRJ, Le Meur Y, Cantarovich M. et al Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol 2010; 5: 341-358 doi:10.2215/CJN.07111009
    CrossrefPubMedGoogle Scholar
  • 24 Wang X, Qin X, Wang Y. et al Controlled-dose versus fixed-dose mycophenolate mofetil for kidney transplant recipients: a systematic review and meta-analysis of randomized controlled trials. Transplantation 2013; 96: 361-367 doi:10.1097/TP.0b013e31828c6dc7
    CrossrefPubMedGoogle Scholar
  • 25 van Gelder T, Hesselink DA. Mycophenolate revisited. Transpl Int 2015; 28: 508-515 doi:10.1111/tri.12554
    CrossrefPubMedGoogle Scholar
  • 26 Daher Abdi Z, Prémaud A, Essig M. et al Exposure to mycophenolic acid better predicts immunosuppressive efficacy than exposure to calcineurin inhibitors in renal transplant patients. Clin Pharmacol Ther 2014; 96: 508-515 doi:10.1038/clpt.2014.140
    CrossrefPubMedGoogle Scholar
  • 27 van Gelder T, Le Meur Y, Shaw LM. et al Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006; 28: 145-154 doi:10.1097/01.ftd.0000199358.80013.bd
    CrossrefPubMedGoogle Scholar
  • 28 Knight SR, Morris PJ. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review. Transplantation 2008; 85: 1675-1685 doi:10.1097/TP.0b013e3181744199
    CrossrefPubMedGoogle Scholar
  • 29 Shaw LM, Korecka M, Venkataramanan R. et al Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2003; 3: 534-542 doi:10.1034/j.1600-6143.2003.00079.x
    CrossrefPubMedGoogle Scholar
  • 30 van Gelder T, Tedesco Silva H, de Fijter JW. et al Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid. Transplantation 2010; 89: 595-599 doi:10.1097/TP.0b013e3181ca7d84
    CrossrefPubMedGoogle Scholar
  • 31 Le Meur Y, 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 doi:10.1111/j.1600-6143.2007.01983.x
    CrossrefPubMedGoogle Scholar
  • 32 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 doi:10.1097/TP.0b013e318186f98a
    CrossrefPubMedGoogle Scholar
  • 33 Gaston RS, Kaplan B, Shah T. et al Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial. Am J Transplant 2009; 9: 1607-1619 doi:10.1111/j.1600-6143.2009.02668.x
    CrossrefPubMedGoogle Scholar
  • 34 Shipkova M, Armstrong VW, Oellerich M, Wieland E. Acyl glucuronide drug metabolites: toxicological and analytical implications. Ther Drug Monit 2003; 25: 1-16 doi:10.1097/00007691-200302000-00001
    CrossrefPubMedGoogle Scholar
  • 35 Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol 2014; 88: 1351-1389 doi:10.1007/s00204-014-1247-1
    CrossrefPubMedGoogle Scholar
  • 36 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
    CrossrefPubMedGoogle Scholar
  • 37 Weber LT, Shipkova M, Lamersdorf T. et al Pharmacokinetics of mycophenolic acid (MPA) and determinants of MPA free fraction in pediatric and adult renal transplant recipients. German Study group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. J Am Soc Nephrol 1998; 9: 1511-1520
    CrossrefPubMedGoogle Scholar
  • 38 Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34: 429-455 doi:10.2165/00003088-199834060-00002
    CrossrefPubMedGoogle Scholar
  • 39 Cattaneo D, Gaspari F, Ferrari S. et al Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients. Clin Transplant 2001; 15: 402-409 doi:10.1034/j.1399-0012.2001.150607.x
    CrossrefPubMedGoogle Scholar
  • 40 Weber LT, Hoecker B, Armstrong VW. et al Validation of an abbreviated pharmacokinetic profile for the estimation of mycophenolic acid exposure in pediatric renal transplant recipients. Ther Drug Monit 2006; 28: 623-631 doi:10.1097/01.ftd.0000246766.12872.12
    CrossrefPubMedGoogle Scholar
  • 41 Liu J, Farmer JD, Lane WS. et al Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991; 66: 807-815 doi:10.1016/0092-8674(91)90124-h
    CrossrefPubMedGoogle Scholar
  • 42 Wiederrecht G, Lam E, Hung S. et al The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci 1993; 696: 9-19 doi:10.1111/j.1749-6632.1993.tb17137.x
    CrossrefPubMedGoogle Scholar
  • 43 Ekberg H, Bernasconi C, Tedesco-Silva H. et al Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant 2009; 9: 1876-1885 doi:10.1111/j.1600-6143.2009.02726.x
    CrossrefPubMedGoogle Scholar
  • 44 Machida M, Takahara S, Ishibashi M. et al Effect of temperature and hematocrit on plasma concentration of FK 506. Transplant Proc 1991; 23: 2753-2754
    PubMedGoogle Scholar
  • 45 Zhao W, Maisin A, Baudouin V. et al Limited sampling strategy using Bayesian estimation for estimating individual exposure of the once-daily prolonged-release formulation of tacrolimus in kidney transplant children. Eur J Clin Pharmacol 2013; 69: 1181-1185 doi:10.1007/s00228-012-1457-5
    CrossrefPubMedGoogle Scholar
  • 46 Capron A, Lerut J, Latinne D. et al Correlation of tacrolimus levels in peripheral blood mononuclear cells with histological staging of rejection after liver transplantation: preliminary results of a prospective study. Transpl Int 2012; 25: 41-47 doi:10.1111/j.1432-2277.2011.01365.x
    CrossrefPubMedGoogle Scholar
  • 47 Stifft F, Stolk LM, Undre N. et al Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation. Transplantation 2014; 97: 775-780 doi:10.1097/01.TP.0000437561.31212.0e
    CrossrefPubMedGoogle Scholar
  • 48 Kuypers DR, Peeters PC, Sennesael JJ. et al Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation 2013; 95: 333-340 doi:10.1097/TP.0b013e3182725532
    CrossrefPubMedGoogle Scholar
  • 49 Prémaud A, Weber LT, Tönshoff B. et al Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches. Pharmacol Res 2011; 63: 216-224 doi:10.1016/j.phrs.2010.10.017
    CrossrefPubMedGoogle Scholar
  • 50 Gielis EM, Ledeganck KJ, De Winter BY. et al Cell-Free DNA: An Upcoming Biomarker in Transplantation. Am J Transplant 2015; 15: 2541-2551 doi:10.1111/ajt.13387
    CrossrefPubMedGoogle Scholar
  • 51 Beck J, Bierau S, Balzer S. et al Digital droplet PCR for rapid quantification of donor DNA in the circulation of transplant recipients as a potential universal biomarker of graft injury. Clin Chem 2013; 59: 1732-1741 doi:10.1373/clinchem.2013.210328
    CrossrefPubMedGoogle Scholar
  • 52 Lo YM, Tein MS, Pang CC. et al Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients. Lancet 1998; 351: 1329-1330 doi:10.1016/s0140-6736(05)79055-3
    CrossrefPubMedGoogle Scholar
  • 53 Ensom MH, Davis GA, Cropp CD, Ensom RJ. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes?. Clin Pharmacokinet 1998; 34: 265-279 doi:10.2165/00003088-199834040-00001
    CrossrefPubMedGoogle Scholar