The Effects of Microbiota Composition on Immunosuppression Protocols in Transplantation

Investigating the Links Between Microbiota Composition and Variability Observed in the Pharmacological Response to Immunosuppressive Therapies in Kidney Transplant Patients.

Solid organ transplantation is the treatment of choice for patients suffering from end-stage organ disease, including for chronic kidney failure. The implementation of effective immunosuppressive therapies has already significantly improved the prognosis for graft survival. However, these therapies are often associated with considerable inter- and intra-individual variability both in terms of response or in terms of pharmacokinetics. Innovative approaches must be considered, such as studying the involvement of intestinal microbiota in the pharmacology of these drugs.

The general aim of the study is therefore to relate the variabilities observed in the pharmacology (mainly pharmacokinetics) of immunosuppressive drugs used in renal transplantation (tacrolimus and mycophenolate mofetil) and the composition of the intestinal microbiota of renal transplant patients.

Study Overview

• Status: Unknown
• Conditions: Immunosuppression; Kidney Transplant; Complications; Transplant Failure
• Intervention / Treatment: Drug: Tacrolimus

Detailed Description

Solid-organ transplantation often requires the implementation of a lifelong immunosuppressive therapy. A combination of tacrolimus (TAC), mycophenolate mofetil (MMF), together with steroids is currently used in over 60% of cases. In some patients however, these therapies are associated with high levels of variability, either in terms of response to treatments or in terms of pharmacokinetics, which remains unexplained. To address the issue, new approaches are being considered, in this study we will investigate the involvement of the intestinal microbiota in the pharmacology of these drugs. This is a particularly promising avenue for drugs with a low therapeutic index and large intra- and inter-individual pharmacokinetic variabilities such as tacrolimus and mycophenolate mofetil. Despite promising preliminary data for tacrolimus, the influence of the gut microbiota in these pharmacokinetic variabilities remains unclear, even less data are available about the involvement of the microbiota in the pharmacokinetics of mycophenolate mofetil.

We expect that this study will produce additional information on the effect of immunosuppression drugs on gut microbiota, and the relationship between microbiota composition and variabilities.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Recruiting
    • Cliniques Universitaires Saint-luc
    • Contact: Michel MOURAD, MD; Phone Number: 003227642213; Email: michel.mourad@uclouvain.be
    • Principal Investigator: Laure ELENS, PhD
    • Principal Investigator: Vincent HAUFROID, MD
    • Sub-Investigator: Laure BINDELS, PhD
    • Sub-Investigator: Serge MOUDIO, MD/PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Kidney transplant patients followed at the Saint-Luc University Clinics and having been transplanted in the abdominal transplant service of the clinics will be recruited for the study.

Description

Inclusion Criteria:

• Patients within 1 to 8 years post transplantation
• Aged between 18 and 75 years old
• Patients receiving tacrolimus and mycophenolate mofetil as part of their immunosuppressive therapy
• French speaking
• BMI between 18 and 30.

Exclusion Criteria:

• Use of tobacco
• Potential Alcohol problems (less than two positive answers to the CAGE questionnaire)
• Use of antibiotic medication within 3 months of the sample collection
• Use of laxative medication within 2 weeks of the sample collection
• Use of anti-fungal medication within 2 weeks of the sample collection
• Pregnant or lactating patients.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tacrolimus / Mycophenolate Mofetil; All patients receive maintenance immunosuppressive treatment of tacrolimus in combination with Mycophenolate Mofetil.	Drug: Tacrolimus; Tacrolimus and Mycophenolate Mofetil are given in accordance with patient's current regimen; Other Names: Mycophenolate Mofetil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study of the links between immunosuppressive drugs pharmacology and intestinal microbiota composition	The general aim of the study is to relate the variabilities observed in the pharmacology (mainly pharmacokinetics) of immunosuppressive drugs used in kidney transplantation (tacrolimus and mycophenolate mofetil) and the composition of the intestinal microbiota of these patients.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify links between oral dosage and concentrations found in feces	Study the concentrations of Tacrolimus and Mycophenolate (MPA) Mofetil in feces and highlight predictors depending on microbiota composition	18 months
Identify genetic factors underlying the links between microbiota and Tacrolimus/Mycophenolate Mofetil	Investigate microbial genes responsible for associations between microbiota composition and immuno-suppressant pharmacology	18 months
Tacrolimus concentrations and microbiota	Identify links between microbiota composition and Tacrolimus concentrations in blood.	18 months
Tacrolimus concentrations and genetic polymorphisms	Identify genetic factors able to influence Tac concentrations in blood.	18 months
Tacrolimus concentration and demographics	Investigate the effect of sex and age on Tac concentrations in blood.	18 months
Mycophenolate Mofetil concentration and microbiota	Identify links between microbiota composition and MPA Mofetil concentration in blood and urine.	18 months
Mycophenolate Mofetil concentration and polymorphisms	Identify genetic factors able to influence MPA Mofetil concentrations in blood and urine.	18 months
Mycophenolate Mofetil concentration and demographics	Investigate the effect of sex and age on MPA Mofetil concentrations in blood and urine.	18 months
Investigate potential markers of kidney function in metabolites	Study metabolomics in urine from patients to identify specific markers of kidney function	18 months

Collaborators and Investigators

• Sponsor: Université Catholique de Louvain
• Investigators: Principal Investigator: Vincent Haufroid, MD, Université Catholique de Louvain

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2020
• Primary Completion (Anticipated): March 1, 2021
• Study Completion (Anticipated): March 1, 2021

Study Registration Dates

• First Submitted: April 21, 2020
• First Submitted That Met QC Criteria: April 21, 2020
• First Posted (Actual): April 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 24, 2020
• Last Update Submitted That Met QC Criteria: April 21, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Tacrolimus; Transplantation; Mycophenolate Mofetil; Kidney transplant; Calcineurin inhibitors
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: Microbiota/TAC/MPA

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
• product manufactured in and exported from the U.S.: No