The Effects of Microbiota Composition on Immunosuppression Protocols in Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Kidney Transplant; Complications, Immunosuppression, Transplant Failure

Intervention / Treatment
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* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tacrolimus / Mycophenolate Mofetil<br>All patients receive maintenance immunosuppressive treatment of tacrolimus in combination with Mycophenolate Mofetil. | Drug: Tacrolimus<br>* Tacrolimus and Mycophenolate Mofetil are given in accordance with patient's current regimen<br>* Other names: Mycophenolate Mofetil;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tacrolimus, Mycophenolate Mofetil, Transplantation, Kidney transplant, Calcineurin inhibitors