Begin typing your search above and press return to search.
Volume: 19 Issue: 8 August 2021


Early Use of Tacrolimus Extended-Release in a Pediatric Kidney Transplant Recipient

Tacrolimus extended-release pharmacokinetics and its once-daily formulation provide beneficial properties, and its use has been evaluated in the adult kidney transplant population. Here, we report a case of successful conversion from tacrolimus immediate-release capsules to tacrolimus extended-release tablets in a pediatric kidney transplant recipient.

Key words : Immunosuppression, Nonadherence, Renal transplantation


The tacrolimus extended-release tablet formulation is a calcineurin-inhibitor immunosuppressant that has been FDA approved for organ rejection prophylaxis in kidney transplant recipients who require conversion from tacrolimus immediate-release formulations in combination with other immunosuppressants.1 Advantages of the tacrolimus extended-release formulation are improved bioavailability, lower peak concentration, and less peak-to-trough fluctuation at a lower daily dose than the twice-daily tacrolimus immediate release capsules.1-6 At this time, there are no published reports or studies evaluating the use of tacrolimus extended-release tablets in the pediatric population.

Case Report

A 15-year-old African American male patient with congenital single kidney received a kidney transplant from a deceased donor. The immunosuppression regimen included induction therapy with alemtuzumab (Campath-1H®; Berlex, Montville, NJ; 30 mg as one single dose) and rapid steroid withdrawal with a steroid-free maintenance regimen consisting of twice-daily tacrolimus immediate-release (Prograf; Astellas Pharma US, Inc., Northbrook, IL, USA) and a mycophenolic acid derivative. The patient received mycophenolate mofetil (CellCept; South San Francisco, CA, USA; 750 mg twice daily) and was started on tacrolimus immediate-release on the evening of postoperative day (POD) 1 (6 mg twice daily; 0.1 mg/kg/d in divided doses) with a goal tacrolimus trough concentration of 8 to 10 ng/mL. Tacrolimus dose adjustments were made under the direction of the pediatric nephrologists. The tacrolimus dose was increased daily starting on POD2. His tacrolimus trough concentrations remained in the 2 to 4 ng/mL range during his hospital stay. By POD4, the tacrolimus dose was 9 mg twice daily, and he had reached a tacrolimus trough concentration of 4.5 ng/mL. The patient was discharged on POD5.

In the outpatient setting, tacrolimus trough concentration remained ≤ 6 ng/mL on a dose of 9 mg twice daily. The patient had ongoing headaches since transplant, and we were concerned with increasing peak serum concentrations with further dose increases. Adjusting to 3 times daily dosing was not realistic for the patient. This regimen would have jeopardized medication adherence considering the challenges of providing a dose during school hours. Thus, the patient was transitioned to tacrolimus extended-release on POD14 at a dose of 16 mg once daily (Envarsus XR®; Veloxis Pharmaceuticals, Horsholm, Denmark). This dose was 89% of the preconversion daily tacrolimus immediate-release dose, which is slightly higher than the recommended 80% in the package insert.1

The tacrolimus trough concentration reached a therapeutic range at 9.2 ng/mL by POD36 on tacrolimus extended-release dose of 24 mg daily. The tacrolimus trough concentrations for 3 months posttransplant are illustrated in Figure 1. The patient’s renal function continued to improve throughout the posttransplant course (Figure 2), and there were no reported adverse effects with the use of tacrolimus extended-release. Headaches were noted as resolved at his first clinic visit after conversion to tacrolimus extended-release.

With the conversion to once-daily tacrolimus, the patient was able to draw his tacrolimus trough concentrations after school and take tacrolimus everyday at 4 PM. This provided flexibility for the patient and his family. It allowed him to adjust his tacrolimus administration times to accommodate his parents’ other commitments, as well as his school schedule and other activities.


Increasing data support the noninferiority of tacrolimus extended-release versus tacrolimus immediate-release in preventing rejection episodes and adverse effects. In addition, pharmacokinetic studies have indicated a more steady concentration over 24-hour periods, with less peak-to-trough fluctuations but similar trough concentrations.1-6 Furthermore, there appears to be less gut CYP3A5 activity in the distal portions of the gastrointestinal tract, allowing for improved absorption of tacrolimus extended-release in recipients with CYP3A5*1 (rapid metabolizers).7 In a previous case series, up to 80% of African American recipients were shown to be rapid metabolizers, carrying the CYP3A5*1 allele.1 Regardless of genotype status, tacrolimus extended-release demonstrated a lower maximum serum concentration, prolonged time the drug is present at the maximum concentration, similar overall exposure, and increased bioavailability compared with tacrolimus immediate-release.8

In the case presented here, several factors contributed to making tacrolimus extended-release an attractive option for maintenance immunosup-pression. We were unable to achieve therapeutic levels with relatively high (9 mg twice daily) doses of tacrolimus immediate-release in an African American recipient, likely to be a rapid metabolizer.8 The patient presented with adverse effects (headaches) at that dose, which may have indicated high peak tacrolimus concentrations.

As an adolescent, the patient is in the highest risk population for medical nonadherence post-transplant.9,10 Nonadherence is a leading risk factor for graft loss, and once-daily tacrolimus formulations have been shown to have better medical adherence.11-14 The once-daily formulation allowed this patient to take his medication in the afternoon and have his blood drawn after school hours. In addition, the total number of tablets/capsules he took per day lessened with the conversion.

There are some limitations to this case report. The tacrolimus extended-release dose adjustments may have occurred more frequently to assist in reaching and maintaining therapeutic range; however, the trough concentrations did increase after conversion to tacrolimus extended-release and after each dose increase. The tacrolimus trough concentration did reach therapeutic range later postoperatively (POD21) than preferred, but this may have been further delayed if the patient was maintained on tacrolimus immediate-release. Also, this pediatric patient was 15 years old and weighed 101 kg, which could be physiologically more reflective of the adult population. Nevertheless, many of his psychosocial features were characteristically adolescent.

This is the first case report of tacrolimus extended-release conversion from tacrolimus immediate-release in a pediatric kidney transplant recipient. The tacrolimus trough concentrations continued to increase to goal with better administration flexibility and no added adverse events. Certainly more studies are required, but this case illustrates several potential advantages of tacrolimus extended-release in the pediatric or adolescent population posttransplant. With further investigation, this agent could become a valuable component of the maintenance immuno-suppressive regimen in pediatric transplant patients.


  1. Envarsus XR® [package insert]. Edison, NJ: Veloxis Pharmaceuticals, Inc; 2016.

  2. Nigro V, Glicklich A, Weinberg J. Improved bioavailability of MELTDOSE once-daily formulation of tacrolimus (LCP-Tacro) with controlled agglomeration allows for consistent absorption over 24 hrs: a scintigraphic and pharmacokinetic evaluation [abstract]. Am J Transplant. 2013;13(S5):339.

  3. Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. 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(2):191-197.
    CrossRef - PubMed
  4. Tremblay S, Nigro V, Weinberg J, Woodle ES, Alloway RR. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study. Am J Transplant. 2017;17(2):432-442.
    CrossRef - PubMed
  5. Budde K, Bunnapradist S, Grinyo JM, et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. Am J Transplant. 2014;14(12):2796-2806.
    CrossRef - PubMed
  6. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013;13(3):760-769.
    CrossRef - PubMed
  7. Thorn M, Finnstrom N, Lundgren S, Rane A, Loof L. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol. 2005;60(1):54-60.
    CrossRef - PubMed
  8. Trofe-Clark J, Brennan D, West-Thielke P, Milone M, Lim M, Bloom R. A randomized cross-over phase 3b study of the pharmacokinetics of once-daily extended release MeltDose® tacrolimus (Envarsus® XR) versus twice-daily tacrolimus in African-Americans (ASERTAA) [abstract]. Am J Transplant. 2015;15(S3).
  9. Dew MA, Dabbs AD, Myaskovsky L, et al. Meta-analysis of medical regimen adherence outcomes in pediatric solid organ transplantation. Transplantation. 2009;88(5):736-746.
    CrossRef - PubMed
  10. Fredericks EM. Nonadherence and the transition to adulthood. Liver Transpl. 2009;15(Suppl 2):S63-69.
    CrossRef - PubMed
  11. Michelon T, Dominguez V, Losekan A, et al. Kidney graft failure due to noncompliance. Transplant Proc. 1999;31(7):3031-3032.
    CrossRef - PubMed
  12. Sellares 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(2):388-399.
    CrossRef - PubMed
  13. 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(2):333-340.
    CrossRef - PubMed
  14. Doesch AO, Mueller S, Akyol C, et al. Increased adherence eight months after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation. Drug Des Devel Ther. 2013;7:1253-1258.
    CrossRef - PubMed

Volume : 19
Issue : 8
Pages : 865 - 867
DOI : 10.6002/ect.2017.0195

PDF VIEW [247] KB.

From the 1Department of Pharmacy, the 2Department of Medicine-Nephrology, and the 3Department of Surgery-Transplant, University of North Carolina Medical Center, Chapel Hill, North Carolina, USA
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Alexander H. Toledo, 4022 Burnett Womack Building, Campus Box 7211, Chapel Hill, NC 27599, USA
Phone: +1 919 966 8008