BACKGROUND: The once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes. METHODS: This open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m(2). The prespecified noninferiority margin was 12.5%. RESULTS: The per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan-Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, -1.6%; 95% confidence interval [CI], -12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, -3.5%; 95% CI, -13.6% to 6.6%) or Arm 4 (difference, -7.1%; 95% CI, -16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m(2)) was the main determinant of composite-endpoint efficacy failure across all arms. CONCLUSIONS: In patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD.

Department of Nephrology Centre Hospitalier Universitaire de Nice Nice France 2 Internal Medicine 2 Nephrology University Medical Center Regensburg Germany 3 General Visceral and Transplantation Surgery Hannover Medical School Hannover Germany 4 Department of Transplantology and Surgery District Public Hospital Poznan Poland 5 Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czech Republic 6 Department of Nephrology Dialysis and Organ Transplantation Toulouse University Hospital Toulouse France 7 Address correspondence to Nassim Kamar M D Department of Nephrology Dialysis and Organ Transplantation Toulouse University Hospital CHU Rangueil TSA 50032 31059 Toulouse Cedex 9 France

Erratum In

Transplantation. 2014 Mar 27;97(6):38 PubMed

See more in PubMed

European Medicines Agency. Committee for Medicinal Products for Human Use (2012). CHMP Pharmacokinetics Working Party (PKWP). Questions and answers: positions on specific questions addressed to the Pharmacokinetics Working Party. London. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf. Accessed May 2012.

Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol 2007; 2: 374. PubMed

Wu MJ, Cheng CY, Chen CH, et al. Lower variability of tacrolimus trough concentration after conversion from Prograf to Advagraf in stable kidney transplant recipients. Transplantation 2011; 92: 648. PubMed

Borra LC, Roodnat JI, Kal JA, et al. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant 2010; 25: 2757. PubMed

Stevenson KS, Glen J, Stevens KK, et al. High tacrolimus intrapatient variability is associated with acute rejection and graft loss (abstract MO-021). Transpl Int 2011. (Suppl 2); 24: 111.

Guirado L, Cantarell C, Franco A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant 2011; 11: 1965. PubMed

Morales JM, Varo E, Lázaro P. Immunosuppressant treatment adherence, barriers to adherence and quality of life in renal and liver transplant recipients in Spain. Clin Transplant 2012; 26: 369. PubMed

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. PubMed

Beckebaum S, Jacob S, Sweid D, et al. Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation. Transpl Int 2011; 24: 666. PubMed

Wlodarczyk Z, Squifflet JP, Ostrowski M, et al. Pharmacokinetics for once-versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial. Am J Transplant 2009; 9: 2505. PubMed

European Medicines Agency. Committee for Medicinal Products for Human Use (2008). Guideline on Clinical Investigation of Immunosuppressants for Solid Organ Transplantation. London. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003593.pdf. Accessed May 2012.

Silva HT, Jr, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007; 7: 595. PubMed

Krämer BK, Charpentier B, Bäckman L, et al. for the Tacrolimus Prolonged Release Renal Study Group. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010; 10: 2632. PubMed

Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562. PubMed

Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535. PubMed

De Greef KE, Ysebaert DK, Vercauteren SR, et al. Effect of immunosuppression on damage, leukocyte infiltration, and regeneration after severe warm ischemia/reperfusion renal injury. Transplant Proc 2002; 34: 791. PubMed

Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55: 713. PubMed

Rostaing L, Cantarovich D, Mourad G, et al. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 2005; 79: 807. PubMed

Vítko S, Klinger M, Salmela K, et al. Two corticosteroid-free regimens—tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil—in comparison with a standard triple regimen in renal transplantation: results of the Atlas study. Transplantation 2005; 80: 1734. PubMed

Vítko S, Wlodarczyk Z, Kyllönen L, et al. Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study. Am J Transplant 2006; 6: 531. PubMed

Rosengard BR, Feng S, Alfrey EJ, et al. Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor. Am J Transplant 2002; 2: 701. PubMed

Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study

Outcomes with Tacrolimus-Based Immunosuppression After Kidney Transplantation from Standard- and Extended-Criteria Donors - A Post Hoc Analysis of the Prospective OSAKA Study

Efficacy and safety of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate- or prolonged-release tacrolimus

Recent advances in kidney transplantation: a viewpoint from the Descartes advisory board

Incidence of Posttransplantation Diabetes Mellitus in De Novo Kidney Transplant Recipients Receiving Prolonged-Release Tacrolimus-Based Immunosuppression With 2 Different Corticosteroid Minimization Strategies: ADVANCE, A Randomized Controlled Trial

See more in PubMed

ClinicalTrials.gov
NCT00717470