• This record comes from PubMed

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

. 2019 Oct ; 33 (10) : e13698. [epub] 20190919

Language English Country Denmark Media print-electronic

Document type Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't

Grant support
Department of Health - United Kingdom

BACKGROUND AND AIMS: This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein. MATERIALS AND METHODS: Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout. RESULTS: The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7). CONCLUSIONS: In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation.

See more in PubMed

Hackl C, Schlitt HJ, Melter M, Knoppke B, Loss M. Current developments in pediatric liver transplantation. World J Hepatol. 2015;7:1509‐1520. PubMed PMC

Kim JJ, Marks SD. Long‐term outcomes of children after solid organ transplantation. Clinics (Sao Paulo). 2014;69(suppl 1):28‐38. PubMed PMC

La Manna G, Todeschini P, Capelli I, et al. Advagraf vs. Prograf immunosuppressive therapy in de novo kidney transplant: a single center experience. J Transplant Technol Res. 2014;4:6‐10.

Kim WR, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 annual data report: liver. Am J Transplant. 2014;14(suppl 1):69‐96. PubMed

Astellas Pharma Europe Ltd . Advagraf 0.5mg, 1mg, 3mg and 5mg prolonged‐release hard capsules summary of product characteristics. https://www.medicines.org.uk/emc/product/345. Accessed May 9, 2019.

Astellas Pharma Europe Ltd . Prograf 0.5mg, 1mg, 5mg hard capsules summary of product characteristics. https://www.medicines.org.uk/emc/product/6720. 2019, Accessed April 17, 2019.

Astellas Pharma Ltd . Modigraf 0.2mg granules for oral suspension summary of product characteristics. https://www.medicines.org.uk/emc/product/461. Accessed May 9, 2019.

Trunečka P, Boillot O, Seehofer D, et al. Once‐daily prolonged‐release tacrolimus (ADVAGRAF) versus twice‐daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant. 2010;10:2313‐2323. PubMed

Urbanowicz T, Baszyńska‐Wachowiak H, Ligowski M, Straburzyńska‐Migaj E, Misterski M, Jemielity M. Comparison of conventional tacrolimus versus prolong release formula as initial therapy in heart transplantation. Ann Transplant. 2014;19:295‐299. PubMed

Albano L, Banas B, Klempnauer JL, Glyda M, Viklicky O, Kamar N. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation. 2013;96:897‐903. PubMed PMC

Stifft F, Stolk L, Undre N, van Hooff JP, Christiaans MH. Lower variability in 24‐hour exposure during once‐daily compared to twice‐daily tacrolimus formulation in kidney transplantation. Transplantation. 2014;97:775‐780. PubMed

Kuypers D, 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. PubMed

Adam R, Karam V, Delvart V, et al. Improved survival in liver transplant recipients receiving prolonged‐release tacrolimus in the European Liver Transplant Registry. Am J Transplant. 2015;15:1267‐1282. PubMed

Shuker N, Shuker L, van Rosmalen J, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long‐term outcome of kidney transplantation. Transpl Int. 2016;29:1158‐1167. PubMed

Pollock‐BarZiv SM, Finkelstein Y, Manlhiot C, et al. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant. 2010;14:968‐975. PubMed

Süsal C, Döhler B. Late intra‐patient tacrolimus trough level variability as a major problem in kidney transplantation ‐ a Collaborative Transplant Study Report. Am J Transplant. 2019. 10.1111/ajt.15346 [Epub ahead of print] PubMed DOI

Zhao W, Elie V, Roussey G, et al. Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther. 2009;6:609‐618. PubMed

Abdel Jalil MH, Hawwa AF, McKiernan PJ, Shields MD, McElnay JC. Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients. Br J Clin Pharmacol. 2014;77:130‐140. PubMed PMC

Shellmer DA, Dabbs AD, Dew MA. Medical adherence in pediatric organ transplantation: what are the next steps? Curr Opin Organ Transplant. 2011;16:509‐514. PubMed PMC

Dobbels F, Damme‐Lombaert RV, Vanhaecke J, Geest SD. Growing pains: Non‐adherence with the immunosuppressive regimen in adolescent transplant recipients. Pediatr Transplant. 2005;9:381‐390. PubMed

Dew MA, Dabbs AD, Myaskovsky L, et al. Meta‐analysis of medical regimen adherence outcomes in pediatric solid organ transplantation. Transplantation. 2009;88:736‐746. PubMed PMC

Fredericks EM. Nonadherence and the transition to adulthood. Liver Transplant. 2009;15(suppl 2):S63‐S69. PubMed

Latin American Pediatric Nephrology Association, Latin American Pediatric Renal Transplant Cooperative Study . Latin American Registry of Pediatric Renal Transplantation 2004‐2008. Pediatr Transplant. 2010;14:701‐708. PubMed

Cao S, Cox KL, Berquist W, et al. Long‐term outcomes in pediatric liver recipients: comparison between cyclosporin A and tacrolimus. Pediatr Transplant. 1999;3:22‐26. PubMed

McDiarmid SV, Busuttil RW, Ascher NL, et al. FK506 (tacrolimus) compared with cyclosporine for primary immunosuppression after pediatric liver transplantation. Transplantation. 1995;59:530‐536. PubMed

Reding R. Tacrolimus in pediatric liver transplantation. Pediatr Transplant. 2002;6:447‐451. PubMed

Vondrak K, Dhawan A, Parisi F, et al. Comparative pharmacokinetics of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate‐ or prolonged‐release tacrolimus. Pediatr Transplant. 2018;22:e13289. PubMed

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. PubMed

Trompeter R, Filler G, Webb N, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol. 2002;17:141‐149. PubMed

Grenda R, Watson A, Trompeter R, et al. A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST study. Am J Transplant. 2010;10:828‐836. PubMed

Kim JS, Aviles DH, Silverstein DM, LeBlanc PL, Matti Vehaskari V. Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients. Pediatr Transplant. 2005;9:162‐169. PubMed

Webb N, Douglas SE, Rajai A, et al. Corticosteroid‐free kidney transplantation improves growth: 2‐year follow‐up of the TWIST randomized controlled trial. Transplantation. 2015;99:1178‐1185. PubMed

Kivelä JM, Räisänen‐Sokolowski A, Pakarinen MP, et al. Long‐term renal function in children after liver transplantation. Transplantation. 2011;91:115‐120. PubMed

Find record

Citation metrics

Loading data ...

Archiving options

Loading data ...