Evaluation of the impact of Tacrolimus-based immunosuppression on Heidelberg liver transplant cohort (HDTACRO): Study protocol for an investigator initiated, non-interventional prospective study

Elias Khajeh, Georgios Polychronidis, Ali Ramouz, Parnian Alamdari, Anastasia Lemekhova, Melisa Saracevic, Sadeq Ali-Hasan-Al-Saegh, Omid Ghamarnejad, Ali Majlesara, Sepehr Abbasi Dezfouli, Arash Nickkholgh, Karl Heinz Weiss, Christian Rupp, Arianeb Mehrabi, Markus Mieth, Elias Khajeh, Georgios Polychronidis, Ali Ramouz, Parnian Alamdari, Anastasia Lemekhova, Melisa Saracevic, Sadeq Ali-Hasan-Al-Saegh, Omid Ghamarnejad, Ali Majlesara, Sepehr Abbasi Dezfouli, Arash Nickkholgh, Karl Heinz Weiss, Christian Rupp, Arianeb Mehrabi, Markus Mieth

Abstract

Background: Tacrolimus-based immunosuppression has resulted in enormous improvements on liver transplantation (LTx) outcomes. However, dose adjustment and medication adherence play a key role in post-transplant treatment success. The aim of the present study is to assess the trough levels and the need for adaptation of therapeutic doses in de novo LTx patients treated with Tacrolimus in the clinical routine, without any intervention to the treatment regimen.

Methods and analysis: This is a pilot, prospective, exploratory, monocentric, non-interventional and non-randomized investigator-initiated study. Prospectively maintained data of 100 patients treated with various oral Tacrolimus-based immunosuppressants (Prograf or Envarsus) will be analyzed. The number of required dose adjustments of Tacrolimus formulations used in clinical routine for achieving the target trough level, Tacrolimus trough level, Tacrolimus dosing, concentration/dose ratio, routine laboratory tests, efficacy data (incl. survival, acute rejection, re-transplantation), patients therapy adherence, and infections requiring the need to reduce individual immunosuppressant dosing will be evaluated for each patient.

Result: This study will evaluate the trough levels and the need for adaptation of therapeutic doses in de novo LTx patients treated with Tacrolimus in the clinical routine, without any intervention to the treatment regimen.

Conclusion: The HDTACRO study will be the first study to systematically and prospectively evaluate various oral Tacrolimus-based immunosuppressants in de novo liver transplanted patients. If a difference between the therapy-subgroups is evident at the end of the trial, a randomized control trial will eventually be designed. Registration number: ClinicalTrials.gov: NCT04444817.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

References

    1. Budde K, Giessing M, Liefeldt L, et al. Modern immunosuppression following renal transplantation. Standard or tailor made? Der Urologe Ausg A 2006;45:9–17.
    1. Londoño M-C, Rimola A, O’Grady J, et al. Immunosuppression minimization vs complete drug withdrawal in liver transplantation. J Hepatol 2013;59:872–9.
    1. Barbier L, Garcia S, Cros J, et al. Assessment of chronic rejection in liver graft recipients receiving immunosuppression with low-dose calcineurin inhibitors. J Hepatol 2013;59:1223–30.
    1. Provenzani A, Santeusanio A, Mathis E, et al. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol 2013;19:9156.
    1. Abouljoud MS, Kumar M, Brayman KL, et al. Neoral® rescue therapy in transplant patients with intolerance to tacrolimus. Clin Transplant 2002;16:168–72.
    1. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004;43:623–53.
    1. Matas A, Smith J, Skeans M. Special issue: organ procurement and transplantation network and scientific registry of transplant recipients 2011 data report. OPTN/SRTR 2011 annual data report: kidney. Am J Transplant 2013;13(11.):
    1. Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit 2009;31:139–52.
    1. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Ther Drug Monit 2001;23:1296–310.
    1. Tielen M, van Exel J, Laging M, et al. Attitudes to medication after kidney transplantation and their association with medication adherence and graft survival: a 2-year follow-up study. J Transplant 2014;2014.
    1. Hardinger KL, Hutcherson T, Preston D, et al. Influence of pill burden and drug cost on renal function after transplantation. Pharmacotherapy 2012;32:427–32.
    1. Morrissey P, Reinert S, Yango A, et al. Factors contributing to acute rejection in renal transplantation: the role of noncompliance. Transplant Proc 2005;37:2044–7.
    1. Vlaminck H, Maes B, Evers G, et al. Prospective study on late consequences of subclinical non-compliance with immunosuppressive therapy in renal transplant patients. Am J Transplant 2004;4:1509–13.
    1. Comuzzi C, Lorenzin D, Rossetto A, et al. Safety of conversion from twice-daily tacrolimus (Prograf) to once-daily prolonged-release tacrolimus (Advagraf) in stable liver transplant recipients. Transplant Proc 2010;42:1320–1.
    1. First MR. First clinical experience with the new once-daily formulation of tacrolimus. Therapeut Drug Monitor 2008;30:159–66.
    1. Baraldo M. Meltdose tacrolimus pharmacokinetics. Transplant Proc 2016;48:420–3.
    1. Gaber AO, Alloway RR, Bodziak K, et al. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation 2013;96:191.
    1. von Einsiedel J, Thölking G, Wilms C, et al. Conversion from Standard-Release Tacrolimus to MeltDose® Tacrolimus (LCPT). Improves Renal Function Liver Transplant 2020;9:1654.
    1. Budde K, Bunnapradist S, Grinyo J, et al. Once daily LCP-Tacro MeltDose® tacrolimus vs. twice daily tacrolimus in de novo kidney transplants: one-year results of phase 3, double-blind, randomized trial. Am J Transplant 2014;14:2796–806.
    1. Feng S, Chapman W, DuBay D. A phase 2 randomized study of the pharmacokinetics, safety and efficacy of Lcp-tacro™ tablets once-a-day vs. Prograf® capsules twice-a-day inde Novoliver transplants. Am J Transplant 2012;12:239–1239.
    1. Rostaing L, Bunnapradist S, Grinyó JM, et al. Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: two-year results of phase 3, double-blind, randomized trial. Am J Kidney Dis 2016;67:648–59.
    1. Kim SH, Lee SD, Kim YK, et al. Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int 2015;14:374–9.
    1. Rodríguez-Perálvarez M, Germani G, Papastergiou V, et al. Early tacrolimus exposure after liver transplantation: relationship with moderate/severe acute rejection and long-term outcome. J Hepatol 2013;58:262–70.
    1. Mehrabi A, Fonouni H, Müller S, et al. Current concepts in transplant surgery. Liver Transplant Today 2008;393:245–60.
    1. Jain A, Reyes J, Kashyap R, et al. Long-term survival after liver transplantation in 4,000 consecutive patients at a single center 2000;232:490.
    1. Moini M, Schilsky ML, Tichy EMJWjoh. Review on immunosuppression in liver transplantation 2015;7:1355.
    1. Abboudi H, MacPhee IAJP. Medicine p. Individualized immunosuppression in transplant patients. Potential Role Pharmacogenet 2012;5:63.
    1. Raichlin E, Daly RC, Rosen CB, et al. Combined heart and liver transplantation: a single-center experience. Transplantation 2009;88:219–25.
    1. Rana A, Robles S, Russo MJ, et al. The combined organ effect: protection against rejection? Ann Surg 2008;248:871–9.
    1. de la Garza RG, Sarobe P, Merino J, et al. Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance. Liver Transpl 2013;19:937–44.
    1. Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol 2016;11:332–43.
    1. McAlister VC, Haddad E, Renouf E, et al. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis 2006;6:1578–85.
    1. Mukherjee S, Mukherjee UJJ. A comprehensive review of immunosuppression used for liver transplantation. J Transplant 2009;2009:1–20.
    1. Muduma G, Saunders R, Odeyemi I, et al. Systematic review and meta-analysis of tacrolimus versus ciclosporin as primary immunosuppression after liver transplant. PLoS One 2016;11:e0160421.
    1. Tolou-Ghamari Z, Sanei BJT. Prograf concentrations in liver transplantation: correlation with headache and other neurotoxic complications. Thrita 2016;5:1–4.
    1. Valente G, Rinaldi L, Sgambato M, Piai G. Conversion from twice-daily to once-daily tacrolimus in stable liver transplant patients: effectiveness in a real-world setting. Transplant Proc 2013;45:1273–5.

Source: PubMed

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