Evaluation of the Impact of Tacrolimus-based Immunosuppression on Heidelberg Liver Transplant Cohort (HDTACRO): Study Protocol for an Investigator Initiated, Non-interventional Prospective Study

Lead sponsor: University Hospital Heidelberg

Modern immunosuppression is characterized by a combination of different immunosuppressants. As a result, the dose of the individual substances, and thus also their side effects can be reduced. Immunosuppression on the basis of low-dose calcineurin inhibitors (CNI) with comparatively low CNI target levels could therefore prevail. Despite all efforts to optimize the treatment regimen after liver transplantation from deceased donors, the amount of medication remains high throughout the postoperative course with CNIs being the main component of immunosuppressive treatment. The main substance used is Tacrolimus in combination with steroids and possibly Mycophenolic acid. Tacrolimus is considered a narrow therapeutic index drug requiring individual dose titration, to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity. Furthermore, transplanted recipients have to remain to a very demanding medication regimen for a long time. The burden of pills required is associated with decreased adherence, and lack of adherence can lead to rejection and possibly graft loss. The aim of present study is to assess the tough levels and need of doses adaptation in de novo liver transplantation with Tacrolimus in the clinical routine, without any intervention in the treatment regimen.

Tacrolimus is considered a narrow therapeutic index drug requiring individual dose titration, to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity. The pharmacokinetic profile of Tacrolimus is characterized by a high degree of inter- and intraindividual variability. Although it is rapidly absorbed, the bioavailability of Tacrolimus in the twice-daily capsule formulation is low and variable, ranging from 17 to 23%. This could be due to poor water solubility, extensive first pass metabolism, p-glycoprotein-mediated efflux and the ingestion of food. Tacrolimus twice-daily capsules are also associated with a characteristic high peak following dosing, which may be associated with increased toxicity.

Furthermore, transplanted recipients have to remain to a very demanding medication regimen for a long time. The burden of pills required is associated with decreased adherence, and lack of adherence can lead to rejection and possibly graft loss.

The development of once-daily Tacrolimus forms without any change of the form of dissolving has already been shown to increase patients' adherence, while little difference has been demonstrated in the Tacrolimus pharmacokinetic profile. The pharmacokinetic profile of Tacrolimus is characterized by flatter kinetics (i.e., less fluctuation and swing) compared to twice-daily Tacrolimus providing for a balanced concentration-time consistency over 24 hours which can also lead to reduced incidence and/or intensity of drug toxicity-related adverse events. Since the development of LCP-Tacrolimus once-daily tablets, with the use of MeltDose® technology, clinical data have shown lower peak and reduced peak-to-tough fluctuations.

• Liver Transplantation

Intervention type: Drug

Intervention name: Tacrolimus

Description: Similar to the clinical routine, as soon as a patient is able to swallow and has a sufficient gastrointestinal activity, Tacrolimus-based immunosuppression using Prograf®, Advagraf® or Envarsus® will be started. Furthermore, calcineurin inhibitors-based immunosuppression will be used (initial dose based on the patients' body weight) with the goal of tough levels of 3-7 ng/mL in the first seven days after liver transplantion, depending on immune status and indication for transplantation. Further tough levels will be determined based on factors such as patients' history and indication for liver transplant.

Arm group label: Tacrolimus-based immunosuppression

Sampling method: Non-Probability Sample

Criteria:

Inclusion Criteria:

- 18 < Recipient Age ≤ 60 years old

- Ability to understand and sign an informed consent form

- Operation and immediate post-operative therapy within the Department of General, Visceral and Transplantion Surgery, University Hospital Heidelberg

- De novo liver transplantation until POD 7

- Immunosuppression after liver transplantation based on Tacrolimus

Exclusion Criteria:

- Re-transplantation

- Acute infection of the biliary tract, pneumonia or CMV infection

Gender: All

Minimum age: 18 Years

Maximum age: 60 Years

Healthy volunteers: No

Last name: Arianeb Mehrabi, MD

Phone: 004962215636223

Email: [email protected]

Germany

June 2020

Responsible party type: Principal Investigator

Investigator affiliation: University Hospital Heidelberg

Investigator full name: Dr. A. Mehrabi

Investigator title: Professsor, Head of the Division of Liver Surgery and Visceral Transplantation

• Tacrolimus
• immunosuppression
• Liver transplantation

Arm group label: Tacrolimus-based immunosuppression

Description: Similar to the clinical routine, as soon as a patient is able to swallow and has a sufficient gastrointestinal activity, Tacrolimus-based immunosuppression using Prograf®, Advagraf® or Envarsus® will be started.

Observational model: Cohort

Time perspective: Prospective