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

Vondrák, Karel; Parisi, Francesco; Dhawan, Anil; Grenda, Ryszard; Webb, Nicholas J.A.; Marks, Stephen D.; Debray, Dominique; Holt, Richard C. L.; Lachaux, Alain; Kelly, Déirdre; Kazeem, Gbenga; Undre, Nasrullah

doi:10.1111/ctr.13698

Cited by 9 publications

(4 citation statements)

References 30 publications

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“…The main finding of this study was that systemic exposure (AUC0-24) was lower for the early post‐transplant period for the prolonged‐release formulation which equalized by 1 month after transplantation. These findings were consistent with those reported in de novo adult transplant recipients ( 9 , 10 ). In adult transplant recipients, the switch from immediate-release tacrolimus to extended-release LCPT tacrolimus was safe and resulted in a 12.5% to 16% increase in the tacrolimus trough level over total daily dose ratio, indicating improved bioavailability ( 11 , 12 ).…”

Section: Introductionsupporting

confidence: 93%

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial

Karaterzi,

Tönshoff,

Ahlenstiel-Grunow

et al. 2024

Front. Nephrol.

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BackgroundTacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation.Methods/designThe study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs).DiscussionThis study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents.Clinical Trial RegistrationEUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

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Section: Introductionsupporting

confidence: 93%

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial

Karaterzi,

Tönshoff,

Ahlenstiel-Grunow

et al. 2024

Front. Nephrol.

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“…In adults the ER‐TAC half‐life is about 35–41 hours 56 . In a pharmacokinetic analysis of 33 pediatric liver, kidney, and heart transplant recipients younger than 16 years, the linear relationship of minimum concentration at 24 hours and AUC at 24 hours showed a strong positive correlation for both IR‐TAC and ER‐TAC, validating trough concentration monitoring for both formulations in the pediatric SOT population 60 . LCP‐tacrolimus (LCP‐TAC; Envarsus XR; Veloxis USA, Cary, NC, USA) is the newest available formulation of a SR, once‐daily TAC melt‐dose tablet has enhanced bioavailability and lower maximum concentrations compared with IR‐TAC.…”

Section: Maintenance Immunosuppression In Pediatric Kidney Transplantmentioning

confidence: 76%

Considerations and controversies of pharmacologic management of the pediatric kidney transplant recipient

2021

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Pediatric kidney transplantation has experienced considerable growth and improvement in patient and allograft outcomes over the past 20 years, in part due to advancements in immunosuppressive regimens and management. Despite this progress, care for this unique population can be challenging due to limited pediatric transplant data and trials, intricacies related to differences in children and adolescents compared with their adult counterparts, and limitations to long‐term survival facing all solid organ transplant populations. Immunosuppression and infection prevention practices vary from one pediatric transplant center to another and clinical controversies exist surrounding treatment and dosing. This review aims to summarize key aspects of pharmacologic management in this population and present pertinent data that describe the influence of practice to serve as a resource for practitioners caring for this unique specialty patient population. Additionally, this review highlights select controversies that exist within pediatric kidney transplantation.

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“…A randomized study compared, in pediatric LTx, immediate-and prolonged-release tacrolimus effects, demonstrating good transplant outcomes over 1 year when prolonged-release tacrolimus was administered. 71 It is well known that the prolonged-release formulation has been associated with reduced intra-patient variability in tacrolimus exposure in adults, improving adherence to treatment and long-term transplant outcomes. [72][73][74] There are limited clinical data in pediatric LTX and reported data are generally from small patient numbers.…”

Section: Most Current Immunosuppression Protocols Are Based On Cnimentioning

confidence: 99%

“…Alternatives could be found in prolonged‐release tacrolimus formulations. A randomized study compared, in pediatric LTx, immediate‐ and prolonged‐release tacrolimus effects, demonstrating good transplant outcomes over 1 year when prolonged‐release tacrolimus was administered 71 …”

Section: Immunosuppressive Regimen Choice and Renal Effectsmentioning

confidence: 99%

Acute and chronic kidney disease after pediatric liver transplantation: An underestimated problem

Lacquaniti

Campo

Tocco

et al. 2020

Clinical Transplantation

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Acute and chronic kidney injuries represent critical issues after liver transplantation (LTx), but whereas renal dysfunction in adult transplant patients is well documented, little is known about its prevalence in childhood. It is a challenge to accurately evaluate renal function in patients with liver disease, due to several confounding factors. Creatinine-based equations estimating glomerular filtration rate, validated in nephropathic patients without hepatic issues, are frequently inaccurate in end-stage liver disease, underestimating the real impact of renal disease. Moreover, whereas renal issues observed within 1 year from LTx were often related to acute injuries, kidney damage observed after 5-7 years from LTx, is due to chronic, irreversible mechanisms. Most immunosuppression protocols are based on calcineurin inhibitors (CNIs) and corticosteroids, but mycophenolate mofetil or sirolimus could play significant roles, also in children. Early diagnosis and personalized treatment represent the bases of kidney disease management, in order to minimize its close relation with increased mortality. This review analyzed acute and chronic kidney damage after pediatric LTx, also discussing the impact of pre-existent renal disease. The main immunosuppressant strategies have been reviewed, highlighting their impact on kidney function. Different methods assessing renal function were reported, with the potential application of new renal biomarkers.

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

Abstract: Background and aims: Thismulticentertrialcomparedimmediate-releasetacrolimus

Cited by 9 publications

References 30 publications

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial

Considerations and controversies of pharmacologic management of the pediatric kidney transplant recipient

Acute and chronic kidney disease after pediatric liver transplantation: An underestimated problem

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