Conversion of Maintenance Prograf to Envarsus in Liver Transplant Recipients

Tacrolimus (Prograf ©) has become part of the standard of care for patients receiving solid organ transplants and is part of the immunosuppressive protocol (along with prednisone and mycophenolate mofetil \[CellCept ©\]) used by liver transplant recipients at University Health Network (UHN). Tacrolimus is associated with several toxicities including renal injury, tremor, pancreatic islet β-cell injury (leading to diabetes) and hyperlipidemia. As a result of these potential toxicities, careful therapeutic drug monitoring of tacrolimus is a key component of post-transplant management. Tacrolimus trough levels are known to correlate with total tacrolimus exposure, as shown from formal pharmacokinetic assessments. Accordingly, trough serum concentrations of tacrolimus are measured routinely in all recipients and are used to guide dosing. The Prograf formulation of tacrolimus has a short serum half-life and must be dosed twice daily to maintain therapeutic serum concentrations. Further, Prograf administration results in a high peak tacrolimus level. Peak tacrolimus levels have been shown to correlate with toxicity; thus, avoidance of high peaks may be desirable to minimize tacrolimus toxicity.

Envarsus is an extended-release formulation of tacrolimus that provides similar drug exposure to tacrolimus at a 30% lower dose but with a once daily dosing regimen. Envarsus dosing also results in a lower peak tacrolimus level compared to Prograf. In this way, it is hoped that Envarsus may provide similar therapeutic efficacy as Prograf but with fewer adverse effects. In addition, the simpler dosing regimen is expected to enhance patient adherence and quality of life.

The present study is aimed at evaluating the impact of a switch from Prograf to Envarsus on liver and renal function, trough tacrolimus levels, drug-related adverse effects and adherence. It hypothesizes that once daily Envarsus can be substituted at reduced daily dose for twice daily Prograf in stable liver transplant recipients without clinically meaningful changes in liver allograft function while reducing tacrolimus side effects, reducing cumulative daily dose of the drug and increasing adherence to treatment and quality of life.The results of this study have the potential to change current practice. Trial design is a pilot randomized trial. The study aims to recruit 40 patients from UHN's LT program and they will be randomized 1:1 to either stay on their current dose of Prograf or be converted to a once-daily equivalent dose of Envarsus. Both groups of patients will be followed for 48 weeks. This study will compare the change from baseline to week 48 in liver and renal function, tacrolimus-related side effects and patient reported outcomes between the two study groups.

• Change in Systolic Blood Pressure [Срок оценки: Baseline to week 24 and week 48]
• Change in Diastolic Blood Pressure [Срок оценки: Baseline to week 24 and week 48]
• Change in Renal function (eGFR) [Срок оценки: Baseline to week 24 and week 48]
• Change in tremor severity (for subset of patients who report significant tremor at baseline) [Срок оценки: Baseline to week 24 and week 48]
• Change in glycemic control (HbA1c) [Срок оценки: Baseline to week 24 and week 48]
• Change in lipid profile [Срок оценки: Baseline to week 24 and baseline to week 48]
• Change in Patient-Reported Outcomes Measurement Information Systems' Pain Interference Bank 2.0 [Срок оценки: Baseline to Week 48 (inclusive)]
• Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Sleep Disturbance Bank 1.0 [Срок оценки: Baseline to Week 48 (inclusive)]
• Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Anxiety Bank 1.0 [Срок оценки: Baseline to Week 48 (inclusive)]
• Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Depression Bank 1.0 [Срок оценки: Baseline to Week 48 (inclusive)]
• Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Global Health Scale version 1.2 [Срок оценки: Baseline to Week 48 (inclusive)]
• Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Fatigue bank 1.0 [Срок оценки: Baseline to Week 48 (inclusive)]