Extended-Release Tacrolimus: same old drug in a different package?

Tacrolimus extended-release capsules 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 XLTM or Advagraf® is modified to be released slowly by adding ethylcellulose, hypromellose, and lactose monohydrate in order to altered 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. Comparable trough levels but lower peak levels were seen with the extended released formulation compared to regular release tacrolimus in two industry 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 lower trough levels and area under the curve (AUC) with the extended release formulation.  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.  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.  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.

Studies have also presented concerning results on more biopsy-proven acute rejections with extended release tacrolimus, and there was speculation that this may be related to the lower peak concentrations. 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. 

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, but improved adherence rates were reported with the use of extended release tacrolimus in liver and heart transplant recipients.

Finally, there is a new formulation of extended release tacrolimus, LCP-TacroTM (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. 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. 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 is associated with significant worse long-term outcomes. Whether utilizing once daily extended release tacrolimus will improve compliance in kidney transplant recipients and consequently improve long-term graft outcome remains to be confirmed.


Miae Kim, MS, PharmD, BCPS
Keri Townsend, PharmD, BCPS
Steven Gabardi, PharmD, FCCP, BCPS
Brigham and Women’s Hospital, Boston, MA