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Published on 22 January 2009

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Modified-release tacrolimus: a new once-daily immunosuppressant for transplant recipients


Initial studies indicate that a new modified-release once-daily formulation of tacrolimus is comparable to the original formulation drug, which had to be taken twice daily

Claudia Rosso

Helio Tedesco-
Silva Junior

José Osmar
Medina Pestana

Nephrology Division
Hospital do Rim e
Universidade Federal de
São Paulo
São Paulo, SP

Advagraf® (modified-release tacrolimus, TACMR, MR4) is a new formulation of modifiedrelease tacrolimus which allows once-daily administration. In healthy volunteers and liver and kidney transplant recipients, the exposure of tacrolimus and trough blood concentration levels were found to be similar after administration of Prograf® or Advagraf. The safety and efficacy of the conversion from Prograf to Advagraf (1:1 mg) was confirmed, as well as their therapeutic equivalence. Tacrolimus mean doses and trough blood concentration levels were similar for Prograf and Advagraf, and patients treated with Prograf or Advagraf were not different with regard to their efficacy or safety profile. Further studies are needed to evaluate the impact of Advagraf on patients’ compliance and whether the pharmacokinetic differences between both formulations can significantly reduce adverse events.

Tacrolimus is an immunosuppressant drug used to prevent acute rejection after solid organ transplantation. Tacrolimus (Prograf) is administered in a twicedaily (bid) regimen and requires routine monitoring of trough blood concentrations to reduce the risk of acute rejection associated with reduced blood concentrations and the risk of adverse events associated with higher blood concentrations. Pharmacokinetic studies have shown that tacrolimus displays chronopharmacokinetics with significant circadian variation. The absorption of tacrolimus is significantly lower after evening administration than after morning administration. This suggests that the administration of a single daily dose could have the same efficacy as the twicedaily regimen, provided that similar morning trough blood concentrations are obtained. Because noncompliance has been associated with a higher risk of graft loss, a once-daily immunosuppressive regimen, by improving compliance, has the potential to prolong graft survival.[1]

Mechanism of action and pharmacodynamics
Tacrolimus is a macrolide immunosuppressant that inhibits cellular and humoral immune responses through several mechanisms of action. Tacrolimus forms a complex with the immunophilin FK506 binding protein 12 (FKBP12), which inhibits the phosphatase activity of calcineurin, a serine-treonine phosphatase. This inhibition prevents nuclear translocation of transcription factors, such as nuclear factor of activated T cells (NFAT), inhibiting activation of the genes
involved in T cell activation, such as interleukin-2.[2]

It has been demonstrated that pharmacodynamic effects on T cell function can be used to monitor immunosuppressants such as tacrolimus, potentially increasing the efficacy and safety of this drug in transplant recipients.[3]

Studies in healthy volunteers
In healthy volunteers, TAC-MR was well tolerated and showed a safety profile similar to Prograf. Single- and multiple-dose studies did not show a difference in tacrolimus exposure (AUC) between TAC-MR and Prograf, being the geometric mean ratio at steady–state [AUC(0–24 h)/(AUCday(0–12 h)+AUCnight(0–12 h))] within the bioequivalence criteria (80–125%) recommended by the FDA (US Food and Drug Administration).
Although peak blood concentrations (Cmax) were lower after administration of TAC-MR, no significant differences were observed in trough concentrations (Cmin) when the two formulations are compared (Figure 1, Table 1). In addition, the correlation between Cmin and AUC was numerically higher after administration of TAC-MR, suggesting that the same target concentration range routinely used for Prograf1 could be used to
guide dose adjustments of TAC-MR.[4]


Conversion from Prograf to TAC-MR in stable
liver and kidney transplant recipients
In stable kidney transplant recipients (n = 70), the conversion from Prograf to TAC-MR, using equivalent total daily doses (1:1) produced similar tacrolimus trough blood concentrations, with no detectable differences in tolerability and safety profiles. At steady state, tacrolimus mean geometric AUC ratio after the administration of TAC-MR or Prograf was 94.7% (Table 1), with no statistical differences in mean trough blood concentrations. High correlations between tacrolimus trough blood concentrations and AUC were observed after administration of Prograf (r >0.80) or TAC-MR (r > 0.86), sustaining the use of Cmin as the surrogate marker for drug exposure to be used for therapeutic monitoring after transplantation.[5] Two other conversion studies with similar design, in liver adult6 and paediatric transplant recipients,[7] showed similar pharmacokinetic results (Table 1).


Studies in de-novo kidney and liver transplant
In a pilot, multicentre, open-label, randomised study that enrolled 66 kidney transplant recipients (Prograf, n = 32 vs TAC-MR, n = 34), no significant differences were observed in tacrolimus AUC, at steady state, between patients receiving these drugs. A good and similar correlation between AUC and Cmin was observed after the administration of TAC-MR or Prograf (r = 0.9 for both formulations).[8] In a similar study involving de-novo liver transplant recipients (Prograf, n = 32 vs TAC-MR, n=45), the incidence of acute rejection was also similar
between the groups,[9] and there were no differences in tolerability and safety profiles comparing the two formulations of tacrolimus.

The therapeutic equivalence (similar incidence of acute rejection and adverse events) of TAC-MR compared to Prograf observed in these pilot studies prompted the initiation of the first phase III, open-label, randomised, prospective and multicentre study, which enrolled 638 de-novo kidney transplant recipients who
were followed for one year.

Patients were enrolled to cyclosporine microemulsion (Neoral®) (n = 214, control group), Prograf (n = 214) or TAC-MR (n = 219). The mean doses of Prograf or TAC-MR required to reach tacrolimus therapeutic concentrations proposed by the study were similar. There were no differences in mean tacrolimus trough blood concentrations or in the proportion of patients reaching study-defined tacrolimus therapeutic ranges between
patients receiving TAC-MR or Prograf. Patients of black ethnicity required higher doses of TAC-MR to reach tacrolimus blood concentrations than did white patients, an observation previously reported for Prograf. These findings confirmed that the same strategy used to make dose adjustments after the administration of Prograf can be used in patients receiving TAC-MR. At the end of the first year, the proportion of patients showing lack of efficacy (composite endpoint of biopsy-proven
acute rejection, graft loss, death or loss of follow-up) was similar for all groups (Table 2). The proportion of patients receiving the randomised treatment at the end of the first year was higher in groups receiving Prograf or TAC-MR. The safety profiles of TAC-MR and Prograf were similar to each other, but clearly distinct from that of cyclosporine (CsA).[10]

These pharmacokinetic and clinical studies demonstrate that the use of TAC-MR, administered in a once-daily regimen, produced similar efficacy and safety to that of Prograf, allowing the use of the same therapeutic monitoring strategy largely applied in transplant recipients receiving Prograf. Future studies enrolling a
larger number of patients monitored for a longer period of follow-up will determine the impact of the once-daily dosing on patients’ compliance and whether the different pharmacokinetic profile of tacrolimus produced by TAC-MR has the ability to reduce the incidence of adverse events, especially long-term nephrotoxicity. Increased compliance and reduced long-term toxicities may have the potential to increase patient and graft survival.


1. Park SI, Felipe CR, Pinheiro-Machado PG, Garcia R, Tedesco-Silva H, Medina-Pestana JO. Circadian and timedependent variability in tacrolimus pharmacokinetics. Fund Clin Pharmacol 2007;21(2):191-7.
2. Cross S, Perry C. Tacrolimus modified release in the prophylaxis of transplant rejection in adult renal or liver allograft recipients. Drugs 2007;67(13):1931- 43.
3. Barten MJ, Tarnok A, Garbade J, Bittner HB, Dhein S, Mohr FW, Gummert JF. Pharmacodynamics of T-cell function for monitoring immunosuppression. Cell Prolif 2007;40(1):50-63.
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7. Heffron TG, Pescovitz MD, Florman S, Kalayoglu M, Emre S, Smallwood G, Wisemandle K, Anania C, Dhadda S, Sawamoto T, Keirns J, Fitzsimmons W, First MR. Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients. Am J Transplant 2007;7(6):1609-15.
8. Undre A For the Tacrolimus Modified Release Kidney Study Group. Use of once a daily modified release tacrolimus regimen in de novo kidney transplant recipients. Am J Transplant 2005;5:190 (Abstract 132).
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