Skip to main navigation menu Skip to main content Skip to site footer

Original article

Vol. 149 No. 4950 (2019)

Immunosuppressant therapeutic drug monitoring and trough level stabilisation after paediatric liver or kidney transplantation

  • Klara M. Posfay-Barbe
  • Henri Baudet
  • Valérie A. McLin
  • Paloma Parvex
  • Hassib Chehade
  • Christophe Combescure
  • Pascal Bonnabry
  • Caroline Fonzo-Christe
DOI
https://doi.org/10.4414/smw.2019.20156
Cite this as:
Swiss Med Wkly. 2019;149:w20156
Published
04.12.2019

Summary

BACKGROUND

Immunosuppressive therapy must be guided by therapeutic drug monitoring (TDM) in paediatric liver (LT) and kidney transplantation (KT) patients to prevent under- and overdosing, which have clinical consequences.

AIM

The purpose of our study was to analyse TDM results in our institutions and evaluate factors associated with blood level stabilisation after LT and KT.

METHODS

Blood levels of immunosuppressants were measured by immunoassay analysis. We compared blood level stabilisation between LT and KT, and evaluated associated factors in a retrospective study in two Swiss university hospitals.

RESULTS

Forty-six patients (27 LT [median age 1.0 y], 19 KT [15.1 y]) were included. During the first month after transplantation, 32.8% (LT) and 41.2% (KT) of tacrolimus, and 22.1% (KT) of ciclosporin trough levels (measured before the next dose) were within target. In KT, trough levels stabilised earlier for tacrolimus than for ciclosporin (p = 0.02). Intensive care and hospital discharge occurred earlier in KT patients (p <0.001). Living-donor LT was associated with an earlier intensive care discharge compared with deceased donor (5.5 vs 11 days, p = 0.02). Primary metabolic disease and graft/recipient weight-ratio ≥0.03 was associated with earlier tacrolimus level stabilisation (14 vs 18 days, p = 0.01 and 15 vs 22 days, p = 0.05, respectively). In KT, recipient age (≥15.1 years) and weight (≥39.4 kg) were associated with an earlier trough level stabilisation (both 13 days vs not reached, p <0.001), and age with earlier hospital discharge (10 vs 14 days, p = 0.02).

CONCLUSION

Immunosuppressant trough levels were often outside the target range in the first month after LT and KT. Organ-specific factors were associated with trough stabilisation.

References

  1. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351(26):2715–29. doi:.https://doi.org/10.1056/NEJMra033540
  2. del Mar Fernández De Gatta M, Santos-Buelga D, Domínguez-Gil A, García MJ. Immunosuppressive therapy for paediatric transplant patients: pharmacokinetic considerations. Clin Pharmacokinet. 2002;41(2):115–35. doi:.https://doi.org/10.2165/00003088-200241020-00004
  3. Snanoudj R, Rabant M, Royal V, Pallet N, Noël LH, Legendre C. Néphrotoxicité des inhibiteurs de la calcineurine : présentation, problèmes diagnostiques et facteurs de risques [Nephrotoxicity of calcineurin inhibitors: presentation, diagnostic problems and risk factors). Nephrol Ther. 2009;5(Suppl 6):S365–70. doi:.https://doi.org/10.1016/S1769-7255(09)73427-3
  4. Tait BD, Hudson F, Cantwell L, Brewin G, Holdsworth R, Bennett G, et al. Review article: Luminex technology for HLA antibody detection in organ transplantation. Nephrology (Carlton). 2009;14(2):247–54. doi:.https://doi.org/10.1111/j.1440-1797.2008.01074.x
  5. OʼLeary JG, Samaniego M, Barrio MC, Potena L, Zeevi A, Djamali A, et al. The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients. Transplantation. 2016;100(1):39–53. doi:.https://doi.org/10.1097/TP.0000000000000869
  6. Rodrigo E, Segundo DS, Fernández-Fresnedo G, López-Hoyos M, Benito A, Ruiz JC, et al. Within-Patient Variability in Tacrolimus Blood Levels Predicts Kidney Graft Loss and Donor-Specific Antibody Development. Transplantation. 2016;100(11):2479–85. doi:.https://doi.org/10.1097/TP.0000000000001040
  7. Touw DJ, Neef C, Thomson AH, Vinks AA ; Cost-Effectiveness of Therapeutic Drug Monitoring Committee of the International Association for Therapeutic Drug Monitoring and Clinical Toxicology. Cost-effectiveness of therapeutic drug monitoring: a systematic review. Ther Drug Monit. 2005;27(1):10–7. doi:.https://doi.org/10.1097/00007691-200502000-00004
  8. Bates DW, Soldin SJ, Rainey PM, Micelli JN. Strategies for physician education in therapeutic drug monitoring. Clin Chem. 1998;44(2):401–7.
  9. Gross AS. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol. 2001;52(Suppl 1):5S–10S. doi:.https://doi.org/10.1046/j.1365-2125.2001.00770.x
  10. Bucuvalas JC, Ryckman FC, Arya G, Andrew B, Lesko A, Cole CR, et al. A novel approach to managing variation: outpatient therapeutic monitoring of calcineurin inhibitor blood levels in liver transplant recipients. J Pediatr. 2005;146(6):744–50. doi:.https://doi.org/10.1016/j.jpeds.2005.01.036
  11. Gross AS. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol. 1998;46(2):95–9. doi:.https://doi.org/10.1046/j.1365-2125.1998.00770.x
  12. Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE ; North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). 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(8):1065–8. doi:.https://doi.org/10.1097/00007890-200104270-00010
  13. Chapman JR. Progress in Transplantation: Will It Be Achieved in Big Steps or by Marginal Gains? Am J Kidney Dis. 2017;69(2):287–95. doi:.https://doi.org/10.1053/j.ajkd.2016.08.024
  14. Mika A, Stepnowski P. Current methods of the analysis of immunosuppressive agents in clinical materials: A review. J Pharm Biomed Anal. 2016;127:207–31. doi:.https://doi.org/10.1016/j.jpba.2016.01.059
  15. Filler G, Alvarez-Elías AC, McIntyre C, Medeiros M. The compelling case for therapeutic drug monitoring of mycophenolate mofetil therapy. Pediatr Nephrol. 2017;32(1):21–9. doi:.https://doi.org/10.1007/s00467-016-3352-2
  16. Larkins N, Matsell DG. Tacrolimus therapeutic drug monitoring and pediatric renal transplant graft outcomes. Pediatr Transplant. 2014;18(8):803–9. doi:.https://doi.org/10.1111/petr.12369
  17. O’Regan JA, Canney M, Connaughton DM, O’Kelly P, Williams Y, Collier G, et al. Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation. J Nephrol. 2016;29(2):269–76. doi:.https://doi.org/10.1007/s40620-015-0230-0
  18. Shuker N, Shuker L, van Rosmalen J, Roodnat JI, Borra LC, Weimar W, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation. Transpl Int. 2016;29(11):1158–67. doi:.https://doi.org/10.1111/tri.12798
  19. Griffin SP, Nelson JE. Impact of a Clinical Solid Organ Transplant Pharmacist on Tacrolimus Nephrotoxicity, Therapeutic Drug Monitoring, and Institutional Revenue Generation in Adult Kidney Transplant Recipients. Prog Transplant. 2016;26(4):314–21. doi:.https://doi.org/10.1177/1526924816667950
  20. Dasari BV, Hodson J, Nassir A, Widmer J, Isaac J, Mergentel H, et al. Variations in Practice to Therapeutic Monitoring of Tacrolimus following Primary Adult Liver Transplantation. Int J Organ Transplant Med. 2016;7(1):1–8.
  21. Andrews LM, Riva N, de Winter BC, Hesselink DA, de Wildt SN, Cransberg K, et al. Dosing algorithms for initiation of immunosuppressive drugs in solid organ transplant recipients. Expert Opin Drug Metab Toxicol. 2015;11(6):921–36. doi:.https://doi.org/10.1517/17425255.2015.1033397
  22. Srinivas NR. Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data. Biopharm Drug Dispos. 2015;36(9):575–86. doi:.https://doi.org/10.1002/bdd.1967
  23. Bessa AB, Felipe CR, Hannun P, Sayuri P, Felix MJ, Ruppel P, et al. A prospective randomized trial investigating the influence of pharmaceutical care on the intra-individual variability of tacrolimus concentrations early after kidney transplant. Ther Drug Monit. 2016;38(4):447–55. doi:.https://doi.org/10.1097/FTD.0000000000000299
  24. Martial LC, Verstegen RH, Cornelissen EA, Aarnoutse RE, Schreuder MF, Brüggemann RJ. A preliminary study searching for the right dose of tacrolimus in very young (≤4 years) renal transplant patients. J Pharm Pharmacol. 2016;68(11):1366–72. doi:.https://doi.org/10.1111/jphp.12639
  25. Albring A, Wendt L, Harz N, Engler H, Wilde B, Kribben A, et al. Relationship between pharmacokinetics and pharmacodynamics of calcineurin inhibitors in renal transplant patients. Clin Transplant. 2015;29(4):294–300. doi:.https://doi.org/10.1111/ctr.12504
  26. Sapir-Pichhadze R, Wang Y, Famure O, Li Y, Kim SJ. Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure. Kidney Int. 2014;85(6):1404–11. doi:.. Correction in: Kidney Int. 2014;89:248. doi:.https://doi.org/10.1038/ki.2013.465
  27. Capron A, Haufroid V, Wallemacq P. Intra-cellular immunosuppressive drugs monitoring: A step forward towards better therapeutic efficacy after organ transplantation? Pharmacol Res. 2016;111:610–8. doi:.https://doi.org/10.1016/j.phrs.2016.07.027
  28. Bruckmueller H, Werk AN, Renders L, Feldkamp T, Tepel M, Borst C, et al. Which Genetic Determinants Should be Considered for Tacrolimus Dose Optimization in Kidney Transplantation? A Combined Analysis of Genes Affecting the CYP3A Locus. Ther Drug Monit. 2015;37(3):288–95. doi:.https://doi.org/10.1097/FTD.0000000000000142
  29. Monostory K, Tóth K, Kiss Á, Háfra E, Csikány N, Paulik J, et al. Personalizing initial calcineurin inhibitor dosing by adjusting to donor CYP3A-status in liver transplant patients. Br J Clin Pharmacol. 2015;80(6):1429–37. doi:.https://doi.org/10.1111/bcp.12747
  30. Chen P, Li J, Li J, Deng R, Fu Q, Chen J, et al. Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients. J Clin Pharm Ther. 2017;42(1):93–7. doi:.https://doi.org/10.1111/jcpt.12480
  31. Liu F, Li Y, Lan X, Wei YG, Li B, Yan LN, et al. Tacrolimus dosage requirements in living donor liver transplant recipients with small-for-size grafts. World J Gastroenterol. 2009;15(31):3931–6. doi:.https://doi.org/10.3748/wjg.15.3931
  32. Morine Y, Shimada M, Torii M, Imura S, Ikegami T, Kanemura H, et al. Optimal administration of tacrolimus in reduced-size liver. Dig Dis Sci. 2009;54(8):1789–93. doi:.https://doi.org/10.1007/s10620-008-0551-0
  33. Wilberg J, Küpper B, Thrum K, Bärthel E, Koch A, Settmacher U, et al. Oral tacrolimus bioavailability is increased after right split liver transplantation. Transplant Proc. 2007;39(10):3237–8. doi:.https://doi.org/10.1016/j.transproceed.2007.03.102
  34. Lancia P, Jacqz-Aigrain E, Zhao W. Choosing the right dose of tacrolimus. Arch Dis Child. 2015;100(4):406–13. doi:.https://doi.org/10.1136/archdischild-2013-305888
  35. Bekersky I, Dressler D, Mekki QA. Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects. J Clin Pharmacol. 2001;41(2):176–82. doi:.https://doi.org/10.1177/00912700122009999
  36. Kimikawa M, Kamoya K, Toma H, Teraoka S. Effective oral administration of tacrolimus in renal transplant recipients. Clin Transplant. 2001;15(5):324–9. doi:.https://doi.org/10.1034/j.1399-0012.2001.150504.x
  37. Pai AL, Rausch J, Tackett A, Marsolo K, Drotar D, Goebel J. System for integrated adherence monitoring: real-time non-adherence risk assessment in pediatric kidney transplantation. Pediatr Transplant. 2012;16(4):329–34. doi:.https://doi.org/10.1111/j.1399-3046.2012.01657.x
  38. Akchurin OM, Melamed ML, Hashim BL, Kaskel FJ, Del Rio M. Medication adherence in the transition of adolescent kidney transplant recipients to the adult care. Pediatr Transplant. 2014;18(5):538–48. doi:.https://doi.org/10.1111/petr.12289
  39. Millner L, Rodriguez C, Jortani SA. A clinical approach to solving discrepancies in therapeutic drug monitoring results for patients on sirolimus or tacrolimus: Towards personalized medicine, immunosuppression and pharmacogenomics. Clin Chim Acta. 2015;450:15–8. doi:.https://doi.org/10.1016/j.cca.2015.07.022

Most read articles by the same author(s)