Twice-daily Tacrolimus and Everolimus Convert to Once-daily Tacrolimus and Everolimus in Liver Transplant Recipient

Study Overview
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Brief Summary
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It has been identified that nonadherence to immunosuppressant regimen may cause long-term graft failure and death in solid organ transplant recipients. Therefore, simplification of the immunosuppression regimen by reducing daily dosing frequency may improve long-term outcome. The investigators will examine pharmacokinetics and safety profiles of stable liver transplant recipients receiving twice-daily TAC with EVR (BID) regimen and then being converted to once-daily TAC with EVR (QD) regimen over a 6-month study period post-conversion.

Detailed Description
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Randomized trial of everolimus (EVR) with reduced tacrolimus (TAC) regimen after liver transplantation has shown similar incidence of composite efficacy failure rate to a standard tacrolimus regimen, but with superior renal function for up to three years. Recent studies have demonstrated comparable efficacy and safety profiles in liver transplant recipients receiving tacrolimus once-daily (QD) and tacrolimus twice-daily (BID) regimens. In kidney transplantation, once daily everolimus (QD) regimen has shown its safety and effectiveness. It has been identified that nonadherence to immunosuppressant regimen may cause long-term graft failure and death in solid organ transplant recipients. Therefore, simplification of the immunosuppression regimen (e.g. TAC with EVR) by reducing daily dosing frequency may improve long-term outcome. However, little is known about the effectiveness and safety of combined TAC and EVR once-daily (QD) regimen in liver transplant recipients. The investigator will examine pharmacokinetics and safety profiles of stable liver transplant recipients receiving twice-daily TAC with EVR (BID) regimen and then being converted to once-daily TAC with EVR (QD) regimen over a 6-month study period post-conversion.

Official Title
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A Six-month, Prospective, Single-center, Pilot Study Determining the Pharmacokinetics and Effectiveness of Twice-daily Tacolimus and Everolimus Regimen Convert to Once-daily Tacrolimus and Everolimus Regimen in Liver Transplant Patients

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: Tacrolimus and Everolimus


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria Stable liver transplant recipients are eligible for inclusion in this study and have to fulfill all of the following criteria: Liver Transplant Recipients have received liver transplantations for at least 6+1 months prior to enrollment Liver Transplant Recipients have no acute rejection episodes within 3 months prior to the enrollment and are clinically stable Liver Transplant Recipients have been treated with twice-daily regimen of tacrolimus(TAC) plus everolimus(EVR) and TAC and EVR trough levels have stayed within targeted ranges for at least 6 weeks prior to enrollment Provide written informed consent prior to inclusion. Liver transplant recipients who are 18-65 years of age of a primary liver transplant Allograft functioning at an acceptable level as defined by the AST, ALT, Total Bilirubin levels ≤3 times ULN prior to enrollment. Abbreviated MDRD eGFR ≥ 30 mL/min/1.73m2. Key exclusion criteria Patients fulfilling any of the following criteria are not eligible for inclusion in this study: Patients who are recipients of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant. Patients who have a combined liver-kidney transplant. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. Existence of any surgical, medical or mental conditions, other than the current transplantation, which, in the opinion of the investigator, might interfere with the objectives of the study. Pregnant or nursing (lactating) women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus and Everolimus BID<br>TAC BID (C0 2.5-5 ng/mL) EVR BID (1.0 mg BID targeted to C0 3-8 ng/mL) Other Names: Prograf Advagraf Zortress Certican | Drug: Tacrolimus and Everolimus<br>* In the TAC and EVR BID arm, everolimus will be initiated at a dose of 1.0 mg BID within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.15 mg/kg BID and then taper to 0.10 mg/kg BID to maintain trough (C0) concentration in the range 2.5-5 ng/mL. In the TAC and EVR QD arm, everolimus will be initiated at a dose of 2.0 mg QD within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.1-0.2 mg/kg/day QD to maintain trough (C0) concentration in the range 2.5-5 ng/mL.<br>* Other names: Certican;|
| Experimental: Tacrolimus and Everolimus QD<br>TAC QD (C0 2.5-5 ng/mL) EVR QD (2.0 mg QD targeted to C0 3-8 ng/mL) Other Names: Prograf Advagraf Zortress Certican | Drug: Tacrolimus and Everolimus<br>* In the TAC and EVR BID arm, everolimus will be initiated at a dose of 1.0 mg BID within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.15 mg/kg BID and then taper to 0.10 mg/kg BID to maintain trough (C0) concentration in the range 2.5-5 ng/mL. In the TAC and EVR QD arm, everolimus will be initiated at a dose of 2.0 mg QD within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.1-0.2 mg/kg/day QD to maintain trough (C0) concentration in the range 2.5-5 ng/mL.<br>* Other names: Certican;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate pharmacokinetic profile of everolimus and tacrolimus in liver transplant recipients on AUC (area under the curve) | Area under the plasma concentration versus time curve (AUC) | 6 month |