With the introduction of modern immunosuppressants into clinical transplantation, the incidence of acute rejection episodes has been reduced and graft and patient survival has markedly improved. The most commonly used backbone of maintenance immunosuppression is tacrolimus, a drug with a narrow therapeutic window where variation in a patient's pharmacokinetics may result in a state of under or over immunosuppression. After the patent for tacrolimus expired, generic substitutes have been developed at lower costs to patients and society. While approval of the original formulations of tacrolimus required vigorous clinical trials of transplant patients, approval of generic versions require only a bioequivalence study performed on a relatively small number of healthy volunteers. In 2012, there were five available formulations of generic tacrolimus ? currently holding a market share in the United States of 67% -- in addition to the brand formulation. The transplant community and public at large have expressed concerns about generic substitute versions of immunosuppressants, in particular tacrolimus. Although, brand to generic and various generic to generic switches of tacrolimus formulations are common, the short- and long-term transplant outcomes for recipients receiving generic tacrolimus substitutes have not been systematically evaluated in well controlled clinical studies. Thus, we propose to conduct a 300-patient, four arm, multicenter prospective randomized open labeled parallel observational study in kidney, heart and liver recipients to compare a) brand tacrolimus with study generic; b) brand tacrolimus with a switch to study generic and c) study generic tacrolimus with a switch to locally formulated generic on key clinical, safety, adherence, pharmacodynamic, and immunologic outcomes over a three-year period. We hypothesize that generic tacrolimus use after transplant does not result in inferior outcomes compared to brand tacrolimus use. In addition to the observational clinical study, we will also conduct behavioral studies to understand how type of immunosuppressant therapy impacts adherence and how patient factors affect both adherence and ultimate graft outcomes. A significant number of recipients at risk for graft rejection including pediatric patients, patients who are ethnic/racial minorities, and patients with higher levels of socioeconomic barriers to transplant will be included in the study. Several novel measurements of immune response will be used in the study. Pharmacokinetic response to tacrolimus, as measured by the activity of Nuclear Factor of Activated T Cells dependent cytokine expression levels, also will be studied. Immunologic response will be assessed by studying peripheral immunophenotype and alloantibody formation and relating these parameters to clinical outcomes and medication non-adherence. The results from this study will help the FDA address public concerns regarding the interchangeability of generic and brand immunosuppressants on successful clinical outcomes.
The most common type of drug to prevent transplant rejection (e.g., immunosuppression) is tacrolimus, with multiple brand and generic formulations available in the United States. With transplant center and public concerns present about whether brand and generic tacrolimus are identical, we propose to conduct an observational study of 300 kidney, heart and liver recipients at two transplant centers randomizing whether patients receive brand, generic, or the combination of brand and generic tacrolimus. We will measure whether transplanted recipients' acute rejection rate and 3-year graft and patient survival differ, measure patients' immune responses, and conduct behavioral studies to understand how type of immunosuppressant therapy impacts adherence and successful clinical outcomes.
