There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

Astellas Pharma Europe Ltd Chertsey UK

BENKAZ Consulting Ltd Cambridge UK

Department of Gastroenterology Hepatology Nutritional Disturbances and Pediatrics The Children's Memorial Health Institute Warsaw Poland

Department of Nephrology Kidney Transplantation and Hypertension The Children's Memorial Health Institute Warsaw Poland

Department of Nephrology Rheumatology and Dermatology Center for Rare Diseases Civil Hospice of Lyon 'Woman Mother Child' Hospital Bron Cedex France

Department of Pediatric Nephrology Great Ormond Street Hospital for Children NHS Foundation Trust London UK

Department of Pediatric Nephrology NIHR Wellcome Trust Manchester Clinical Research Facility Manchester Academic Health Science Centre Royal Manchester Children's Hospital University of Manchester Manchester UK

Department of Pediatrics 1 University Children's Hospital Heidelberg Heidelberg Germany

Department of Pediatrics 2nd School of Medicine University Hospital Motol Charles University Prague Czech Republic

Department of Pediatrics ISMETT IRCCS Palermo Italy

Pediatric Cardiology Unit APHP Hôpital Universitaire Necker Paris France

Pediatric Hepatology Gastroenterology and Transplantation Civil Hospice of Lyon Lyon France

Pediatric Hepatology Gastroenterology and Transplantation Hospital Papa Giovanni XXIII Bergamo Italy

Pediatric Hepatology Unit APHP Hôpital Universitaire Necker Paris France

The Liver Unit Birmingham Women's and Children's Hospital Birmingham UK

Unité de Chirurgie et Transplantation Pédiatrique Cliniques Universitaires Saint Luc Université Catholique de Louvain Brussels Belgium

Zobrazit více v PubMed

Kim WR, Lake JR, Smith JM, et al OPTN/SRTR 2016 annual data report: liver. Am J Transplant 2018; 18: 172. PubMed

Hart A, Smith JM, Skeans MA, et al OPTN/SRTR 2016 annual data report: kidney. Am J Transplant 2018; 18: 18. PubMed PMC

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

US Food and Drug Administration . Astagraf XL prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204096s005lbl.pdf. Accessed February 14, 2019.

Astellas Pharma Europe Ltd . Advagraf 0.5 mg, 1 mg, 3 mg and 5 mg prolonged‐release hard capsules summary of product characteristics. https://www.medicines.org.uk/emc/product/345/smpc. Accessed February 20, 2019.

Butler JA, Roderick P, Mullee M, et al Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation 2004; 77: 769. PubMed

Shemesh E, Duncan S, Anand R, et al Trajectory of adherence behavior in pediatric and adolescent liver transplant recipients: the medication adherence in children who had a liver transplant cohort. Liver Transpl 2018; 24: 80. PubMed PMC

Chisholm‐Burns MA, Spivey CA, Rehfeld R, et al Immunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients. Am J Transplant 2009; 9: 2497. 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

Beckebaum S, Iacob 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

Eberlin M, Otto G, Krämer I. Increased medication compliance of liver transplant patients switched from a twice‐daily to a once‐daily tacrolimus‐based immunosuppressive regimen. Transplant Proc 2013; 45: 2314. 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

Kurnatowska I, Krawczyk J, Oleksik T, et al Tacrolimus dose and blood concentration variability in kidney transplant recipients undergoing conversion from twice daily to once daily modified release tacrolimus. Transplant Proc 2011; 43: 2954. PubMed

Alloway R, Steinberg S, Khalil K, et al Conversion of stable kidney transplant recipients from a twice daily Prograf‐based regimen to a once daily modified release tacrolimus‐based regimen. Transplant Proc 2005; 37: 867. PubMed

Florman S, Alloway R, Kalayoglu M, et al Conversion of stable liver transplant recipients from a twice‐daily Prograf‐based regimen to a once‐daily modified release tacrolimus‐based regimen. Transplant Proc 2005; 37: 1211. PubMed

Heffron TG, Pescovitz MD, Florman S, et al Once‐daily tacrolimus extended‐release formulation: 1‐year postconversion in stable pediatric liver transplant recipients. Am J Transplant 2007; 7: 1609. PubMed

Quintero J, Juampérez J, Ortega J, et al Conversion from twice‐daily to once‐daily tacrolimus formulation in pediatric liver transplant recipients – a long‐term prospective study. Transpl Int 2018; 31: 38. PubMed

Carcas‐Sansuán AJ, Hierro L, Almeida‐Paulo GN, et al Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1‐year follow‐up. Liver Transplant 2013; 19: 1151. PubMed

Pape L, Heidotting N, Ahlenstiel T. Once‐daily tacrolimus extended‐release formulation: 1 year after conversion in stable pediatric kidney transplant recipients. Int J Nephrol 2011; 2011: 126251. PubMed PMC

Min SI, Ha J, Kang HG, et al Conversion of twice‐daily tacrolimus to once‐daily tacrolimus formulation in stable pediatric kidney transplant recipients: pharmacokinetics and efficacy. Am J Transplant 2013; 13: 2191. PubMed

Carcas‐Sansuán AJ, Espinosa‐Román L, Almeida‐Paulo GN, et al Conversion from Prograf to Advagraf in stable paediatric renal transplant patients and 1‐year follow‐up. Pediatr Nephrol 2014; 29: 117. PubMed

Rubik J, Debray D, Iserin F, et al Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus to prolonged‐release tacrolimus formulation. Pediatr Transplant 2019; 23: e13391. PubMed

Schwartz GJ, Haycock GB, Edelmann CM Jr., et al A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976; 58: 259. PubMed

US National Institutes of Health . Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Published 2010. Accessed April 17, 2019.

Sellarés J, de Freitas DG, Mengel M, et al Understanding the causes of kidney transplant failure: the dominant role of antibody‐mediated rejection and nonadherence. Am J Transplant 2012; 12: 388. PubMed

Wiebe C, Gibson IW, Blydt‐Hansen TD, et al Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor‐specific antibody. Am J Transplant 2015; 15: 2921. PubMed

Kuypers DR, Claes K, Evenepoel P, et al Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long‐term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther 2004; 75: 434. PubMed

Dirks NL, Huth B, Yates CR, et al Pharmacokinetics of immunosuppressants: a perspective on ethnic differences. Int J Clin Pharmacol Ther 2004; 42: 701. PubMed

Mancinelli LM, Frassetto L, Floren LC, et al The pharmacokinetics and metabolic dispostion of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther 2001; 69: 24. PubMed

Andrews LM, De Winter BC, Van Gelder T, et al Consideration of the ethnic prevalence of genotypes in the clinical use of tacrolimus. Pharmacogenomics 2016; 17: 1737. PubMed

Laftavi MR, Pankewycz O, Patel S, et al African American renal transplant recipients (RTR) require higher tacrolimus doses to achieve target levels compared to white RTR: does clotrimazole help? Transplant Proc 2013; 45: 3498. PubMed

Narayanan M, Pankewycz O, El‐Ghoroury M, et al Outcomes in African American kidney transplant patients receiving tacrolimus and mycophenolic acid immunosuppression. Transplantation 2013; 95: 566. PubMed

Beermann KJ, Ellis MJ, Sudan DL, et al Tacrolimus dose requirements in African‐American and Caucasian kidney transplant recipients on mycophenolate and prednisone. Clin Transplant 2014; 28: 762. PubMed

Vadivel N, Garg A, Holt DW, et al Tacrolimus dose in black renal transplant recipients. Transplantation 2007; 83: 997. PubMed

Kim JS, Aviles DH, Silverstein DM, et al Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients. Pediatr Transplant 2005; 9: 162. PubMed

Zhang R. Donor‐specific antibodies in kidney transplant recipients. Clin J Am Soc Nephrol 2018; 13: 182. PubMed PMC