Improved bioavailability and reduced dose requirements of novel, once-daily, meltdose® tacrolimus formulation tablets (envarsus® xr) compared to twice-daily tacrolimus capsules (prograf®) in de novo kidney transplantation: Results of a phase 3 double-dummy, randomized trial

Tacrolimus (tac) is an immunosuppressive drug with a narrow therapeutic range. Adequate trough levels following kidney transplantation (≥6 ng/mL depending on regimen and time post-transplant) are required to prevent against rejection while Cmax cannot be too high (generally <12ng/mL) or else there is risk for toxicity and adverse events. Contributing to tac dosing challenges are suboptimal pharmacokinetics (PK; e.g., low bioavailability, high fluctuation) of the traditional twice-daily capsule formulation (Prograf®) and differences in tac metabolism among specific patient populations (e.g., African Americans; females). Envarsus® XR is an extended-release, once-daily, formulation of tac that uses a novel MeltDose® drug delivery technology which decreases drug particle size down to a molecular level resulting in improved absorption and once-daily dosing. Randomized trials in de novo and stable kidney transplant recipients have shown increased bioavailability, reduced Cmax and noninferior efficacy and similar safety as Prograf, at a reduced total daily dose (TDD). The purpose of the present analysis was to examine dosing and bioavailability (trough/TDD) of tac over a two year period in de novo kidney recipients randomized to Envarsus XR or Prograf. Immediately post-transplant, target tac trough levels were more rapidly achieved in the Envarsus XR group. From Week 3 onward, TDDs were lower for Envarsus XR and the difference between the two groups increased over time. By month 24, the mean TDD for Envarsus XR was 24% lower than the Prograf group, yet troughs (ng/mL) were similar (5.5 vs. 5.7, respectively). These data show that Envarsus XR is associated with continued improved absorption/bioavailability, resulting in the requirement for a lower (Figure Presented).