Assessment of the Pharmacokinetic Profile of Tacrolimus Medications and Their Relation to Effectiveness and Safety in Liver Transplant Patients (LTA)

Assessment of the Pharmacokinetic Profile of Tacrolimus Medications in Liver Transplant Patients

The goal of this observational study is oo compare the pharmacokinetic parameters of different tacrolimus containing medications in liver transplant patients. The main question[s] it aims to answer are:

• Differences in pharmacokinetic parameters of tacrolimus containing medicinal products (TL, TDD and their ratio - C/D)
• Changes in liver function parameters compared to baseline.
• Change in the estimated glomerular filtration rate (eGFR) compared to baseline.
• To assess the possible relation of liver function parameters and eGFR to C/D (blood concentration and daily dosage)
• Incidence of acute graft rejection during the study
• Incidence of BK and cytomegalovirus (CMV) infection during the study
• To assess the intraindividual variability of the TL, TDD and the ratios of these parameters (C/D)
• To assess the patient-adherence of therapy based on the BAASIS questionnaire, and prescription filled by individual patients, based on electronic health-care record.

Participants will not have to undergo any additional clinical visits or tests except which are required in routine clinical care

Study Overview

• Status: Recruiting
• Conditions: Liver Failure
• Intervention / Treatment: Drug: Tacrolimus

Detailed Description

The primary aim of the study is to assess tolerability of LCPT and graft function within the 24-month observational period. Other objectives include the assessment of the intraindividual variability of the TL and TDD, the incidence of BK and cytomegalovirus infections, the incidence of graft insufficiency and acute and chronic graft rejection. There are few real-life studies available on maintenance treatment regimens in liver transplant patients throughout Europe, and these only focus on the healthcare resources' consumption. There is a lack of data describing the effectiveness of different drugs and their combinations in early maintenance immunosuppression in the real-life setting. Even less data is available of ISU (immunosuppression) drugs combinations' metabolism and its relation to effectiveness and safety, measured in liver transplant patients.

Given the above considerations we planned this non-interventional study (NIS) to assess pharmacokinetic parameters of LCPT and other tacrolimus containing medications and their relation to efficacy and tolerability in hepatic allograft recipients in a real-life setting.

• Study Type: Observational
• Enrollment (Estimated): 110

Contacts and Locations

• Study Contact: Name: Ákos Szeredi, MD; Phone Number: +36707772232; Email: a.szeredi@chiesi.com

Study Locations

• Hungary
  • Budapest, Hungary, 1085
    • Recruiting
    • Semmelweis University, Department of Surgery, Transplantation and Gastroenterology
    • Contact: László Piros, MD, PhD; Phone Number: +36300905499; Email: drpiroslaszlo@gmail.com
    • Sub-Investigator: Tamás Benkő, MD, PhD
    • Sub-Investigator: Anita Haboub Sandil, MD
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Recruiting
    • University Medical Center Ljubljana, Division of Internal Medicine, Department of Gastroenterology
    • Contact: Marija Ribnikar, MD, PhD
    • Sub-Investigator: Katja Novak, MD
    • Sub-Investigator: Jan Drnovsek, MD
    • Sub-Investigator: Anja Rihtarsic, MD
    • Sub-Investigator: Marjana Turk Jerovsek, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Adult, liver (or concomittant liver-renal) transplant patients, receiving tacrolimus containing medications.

Description

Inclusion Criteria:

1. Patients ≥ 18 years of age
2. Patients after liver- or simultaneous liver and kidney transplantation
3. Having received a tacrolimus containing immunosuppressant therapeutic regimen at least for four weeks (induction therapy), and TL is within 5-20 ng/ml before inclusion
4. Patients signed an informed consent form for use of their pseudonymised clinical data within the present non-interventional trial.

Exclusion Criteria:

1. Participation in any clinical trial, 30 days prior to inclusion
2. The patients received liver allograft more than 6 months before inclusion
3. Hospitalisation due to infection, acute rejection, or graft disfunction 2 weeks prior to enrolment
4. Chronic graft insufficiency in the patient's history
5. Use of medications 2 weeks prior to enrolment, or the need for continuous use of medications that are known to significantly affect the pharmacokinetics of tacrolimus containing medications (as CYP3A4 inducers: rifampin, carbamazepine, phenobarbital, and phenytoin, or CYP3A4 inhibitors: erythromycin, ketoconazole, clarithromycin, and verapamil containing medication)

6. Presence of the following comorbidities:

   1. Diseases affecting adherence to therapy (Chronic neurologic conditions, Psychiatric diseases)
   2. Diseases affecting drug absorption and metabolism (Inflammatory bowel disease, Chronic inflammatory diseases of bile ducts, Presence of ascites due to any disease)
7. Patients on waiting list for re-transplantation

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Liver transplant patients, receiving tacrolimus containing immunosuppression; Patients ≥ 18 years of age; Patients after liver- or simultaneous liver and kidney transplantation; Having received a tacrolimus containing immunosuppressant therapeutic regimen at least for four weeks (induction therapy), and TL is within 5-20 ng/ml before inclusion. Possible medications are the following (dosages and administration according to local (European) SmPCEnvarsus prolonged release tabletAdport hard capsuleAdvagraf prolonged-release hard capsuleModigraf granule for oral suspensionPrograf hard capsuleTacforius hard capsule

Drug: Tacrolimus; Tacrolimus received as part of routine clinical care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic profile TL	To compare the trough level (TL) of different tacrolimus containing medications to Envarsus at each visit	12 months
Pharmacokinetic profile TDD	To compare the total daily dose (TDD) of different tacrolimus containing medications to Envarsus at each visit	12 months
Pharmacokinetic profile C/D	To compare the ration of TL and TDD (C/D) of different tacrolimus containing medications to Envarsus at each visit	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver function GGT	Changes in Gamma glutamine transferase (GGT) levels compared to baseline.	12 months
Liver function AP	Changes in Alcalic phosphatase (AP) levels compared to baseline.	12 months
Liver function GOT	Changes in Glutamyl oxaloacetic transaminase (GOT) levels compared to baseline.	12 months
Liver function GPT	Changes in Glutamyl pyruvic transaminase (GPT) levels compared to baseline.	12 months
Renal function	Change in the estimated glomerular filtration rate (eGFR) compared to baseline.	12 months
Kinetics and function	To assess the possible relation of liver function parameters and eGFR to C/D (blood concentration and daily dosage)	12 months
Rejection	Incidence of acute graft rejection during the study	12 months
Virus infection	Incidence of BK and cytomegalovirus (CMV) infection during the study	12 months
Variability	To assess the intraindividual variability of the TL, TDD and the ratios of these parameters (C/D)	12 months
Adherence BAASIS	To assess the patient-adherence of therapy based on the BAASIS questionnaire	12 months
Adherence prescriptions	To assess the patient-adherence of therapy based on the prescription filled by individual patients, based on electronic health-care record.	12 months

Collaborators and Investigators

• Sponsor: Chiesi Hungary Ltd.
• Collaborators: Chiesi Slovenija, d.o.o.
• Investigators: Principal Investigator: László Piros, MD, PhD, Semmelweis University, Department of Surgery, Transplantation and Gastroenterology, Budapest, Hungary

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: January 30, 2023
• First Submitted That Met QC Criteria: February 15, 2023
• First Posted (Actual): February 27, 2023

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 21, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Liver transplantation; Immunosuppression; Tacrolimus
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Liver Diseases; Liver Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: LTA_2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No