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Extended Release Tacrolimus (Astagraf XL™, Advagraf®: Same Old Drug in a Different Package?


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Miae Kim, MS, PharmD, BCPS
Heart Transplant/VAD Pharmacist
Brigham and Women's Hospital
Boston, MA, USA
rlaaldo@gmail.com



Tacrolimus extended-release capsules (Astagraf XL™, Astellas Pharm US, Inc. Northrook, IL) were approved in the US by the Food and Drug Administration (FDA) in July 2013. The development of this new formulation garnered interest due to a possible improvement in immunosuppressive medication compliance. This formulation has been approved for use in European countries since 2007 under the trade name Advagraf®, and it has been approved for use in 73 countries worldwide.

Astagraf XL™ or Advagraf® is modified to be released slowly by adding ethylcellulose, hypromellose, and lactose monohydrate in order to modify water penetration and form a protective polymer coating around the drug. Extended release tacrolimus has different dissolution properties and is delivered in a more distant area of the gastrointestinal tract [1]. Comparable trough levels but lower peak levels were seen with the extended released formulation compared to regular release tacrolimus in two industrial sponsored clinical trials. The trials showed an equivalent overall drug exposure between the two formulations in spite of the lower peak levels with extended release tacrolimus, and suggested a 1:1 conversion from the regular tacrolimus formulation to extended released tacrolimus and the same therapeutic drug monitoring strategy.

Subsequent clinical trials have, however, consistently reported low trough levels and area under the curve (AUC) with the extended release formulation [2]. On average, the trough tacrolimus level with the extended release formulation was 40% lower than that of regular release tacrolimus at 6 weeks post transplant [2]. The total daily dose requirement also tended to be at least 10% higher with extended release tacrolimus as compared to the regular release tacrolimus at 1 year post transplant [2]. One conversion trial among heart transplant recipients used a 1:1.25 dose conversion ratio between regular tacrolimus and extended release tacrolimus to avoid under-immune suppression post conversion, but this did not prevent the need for subsequent dose modifications [3].

Additionally, although a high correlation between trough and AUC was reported with the extended formulation in phase I trials with healthy subjects, significant inter-subject variability in PK profiles and the trough to AUC ratio has been observed with extended release tacrolimus in solid organ transplant recipients, which leads to a concern that monitoring troughs of this drug may not represent the overall exposure to it [1].

Studies have also presented concerning results on more biopsy-proven acute rejections with extended release tacrolimus [4-6], and there was speculation that this may be related to the lower peak concentrations [1]. However, a recent meta-analysis of 6 randomized controlled trials and 15 observational studies found a non-significant difference in biopsy proven acute rejections and graft/patient survivals at 12 months between the two formulations [2].

Considering the relatively low peak obtained from using extended release tacrolimus, it was hypothesized that there may be a beneficial impact on preventing peak-related complications of tacrolimus. In an animal model, reducing tacrolimus peak levels was related to a lower incidence of hyperglycemia [7]. A meta analysis, however, showed that the observed incidence of new-onset diabetes after transplantation was not different [4]. Some studies reported better renal function with the extended release tacrolimus formulation early post renal transplant, but the benefit did not last until 1 year post transplant [4,8]. Additionally, the incidence of bacterial infection was significantly lower among patients receiving extended release tacrolimus [4].

There have been a small number of studies that investigated whether the once daily regimen with extended release tacrolimus instead of twice daily dosing actually improved patient compliance to immunosuppressive regimens. There are no data to suggest that extended release daily tacrolimus improves medication adherence compared with the twice daily tacrolimus formulation in kidney transplant recipients [2], but improved adherence rates were reported with the use of extended release tacrolimus in liver and heart transplant recipients [9,10].

Finally, there is a new formulation of extended release tacrolimus, LCP-Tacro™ (Veloxis Pharmaceuticals, Hørsholm, Denmark), being developed for use in kidney (Phase III) and liver (Phase II) transplant recipients. LCP-tacrolimus has greater bioavailability than regular release tacrolimus, and only requires about 70% of the daily dose of regular release tacrolimus on average [11]. The release of LCP-tacrolimus, which has small size particles of the drug embedded in the tablet being absorbed consistently over a full day, provides a time-to-concentration plot that is similar to that of a continuous infusion of intravenous tacrolimus, with significantly lower peak to trough variations [11,12]. It will be interesting to see how this medication impacts transplant outcomes, safety, and medication compliance.

Nonadherence to immunosuppressive medications is not uncommon in organ transplant recipients, and it can significantly worsen long-term outcomes. It is known that choosing a simpler yet effective regimen is preferred by patients and improves adherence. Utilizing once daily extended release tacrolimus products may be beneficial for improving immunosuppressive medication adherence without compromising graft/patient survivals or patient safety in patients at a high risk of medication noncompliance. More studies are needed to confirm this.

Disclosure Statement: the author has no conflicts of interest to report.


References:

  1. Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 2011;12:1561-77.
  2. Ho ET, Wong G, Craig JC, et al. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation 2013;9:1120-8.
  3. Marzoa-Rivas R, Paniagua-Martin MJ, Barge-Caballero E, et al. Conversion of heart transplant patients from standard to sustained-release tacrolimus requires a dosage increase. Transplantation proceedings 2010;8:2994-6.
  4. Silva HT, Jr., Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. American journal of transplantation: 2007;3:595-608.
  5. Trunecka P, Boillot O, Seehofer D, et al. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. American journal of transplantation: 2010;10:2313-23.
  6. Kramer BK, Charpentier B, Backman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. American journal of transplantation: 2010;12:2632-43.
  7. Ishibashi M, Yoshida K, Ozono S, et al. Experimental study of tacrolimus immunosuppression on the mode of administration: efficacy of constant intravenous infusion avoiding C(max). Transplantation proceedings 2001;1-2:559-60.
  8. Cabello M, Garcia P, Gonzalez-Molina M, et al. Pharmacokinetics of once- versus twice-daily tacrolimus formulations in kidney transplant patients receiving expanded criteria deceased donor organs: a single-center, randomized study. Transplantation proceedings 2010;8:3038-40.
  9. 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. Transplant international: 2011;7:666-75.
  10. Doesch AO, Mueller S, Konstandin M, et al. Increased adherence after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation: a pre-experimental study. Transplantation proceedings 2010;10:4238-42.
  11. Gaber AO, Alloway RR, Bodziak K, et al. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation 2013;2:191-7.
  12. 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. American journal of transplantation: 2013;3:760-9.



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