Immunosuppressive Drugs and Gut Microbiome: Pharmacokinetic- and Microbiome Diversity Effects

Study Overview
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Brief Summary
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Kidney transplant recipients of living- and deceased donor grafts and treated with both mycophenolate mofetil (MMF) and tacrolimus (Tac) will be included. A 12-hour pharmacokinetic (PK) investigation of both mycophenolate (MPA) and Tac will be performed in pharmacokinetic steady state conditions between 3 to 8 weeks and one year after transplantation. Feces samples will be collected before (if possible), 1 week after transplantation and at the day of the 12-hour PK investigations. Data on dietary intake and physical activity will be obtained in association with the feces sampling in all patients. Patients will be invited to a follow-up visit one year after transplantation where the 12-hour PK investigation, feces sampling, dietary and activity data collection is repeated. Standard follow-up data after renal transplantations, such as acute rejection episodes, infections, renal function, post transplant diabetes mellitus (PTDM), protocol biopsies, adherence to immunosuppressive drugs, graft loss and death will be collected for all patients up to 5 years after transplantation according to standard schedule at the transplant center. A subgroup of kidney transplant recipients scheduled for living donor transplantation will be included before transplantation for pre-transplant investigations in addition to the investigations after transplantation. These patients will be randomized to either receive one week of treatment with MMF or Tac before transplantation. Feces samples and a 12-hour PK investigation will be performed after one week of treatment (before transplantation).

Detailed Description
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The analyses of feces samples will be performed by utilizing shotgun, next generation sequencing in order to determine the bacterial, fungal sand viral microbiome. Drug concentrations will be analyzed with high performance Liquid chromatography With double mass spectrometry detector (HPLC-MS/MS) technology and both free and total plasma MPA concentrations, total mycophenolate glucoronide (MPAG) concentrations and total whole blood Tac and methylated Tac-metabolite concentrations will be determined.

Official Title
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Immunosuppressive Drugs and Gut Microbiome: Pharmacokinetic- and Microbiome Diversity Effects

Conditions
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Kidney Transplant; Complications, Immune Suppression

Intervention / Treatment
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* Drug: Mycophenolate Mofetil 500 mg Tab
* Drug: Tacrolimus capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: De novo standard risk kidney transplant recipients. Patients scheduled to receive tacrolimus and mycophenolate mofetil as part of their immunosuppressive therapy following transplantation (clinical decision not influenced by this study). First kidney transplant only. Adult patients. Exclusion Criteria: - Pregnant or lactating female patients.

Ages Eligible for Study
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Minimum Age: 18 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: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: The main study is based on treatment allocation outside of thsi protocol but a subgroup of living donor recipients will be randomized to wither one week tacrolimus or mycophenolate mofetil treatment before transplantation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mycophenolate mofetil<br>In the subgroup of living donor recipients included before transplantation this group will be treated with mycophenolate mofetil (750 mg BID) for one week | Drug: Mycophenolate Mofetil 500 mg Tab<br>* Twice daily dosing of MMF only for a week before transplantation in this subgroup. All patients will get maintenance treatment With MMF in combination With tacrolimus and steroids after transplantation.<br>* Other names: MMF-arm;|
| Active Comparator: Tacrolimus<br>In the subgroup of living donor recipients included before transplantation this group will be treated with tacrolimus (BID, dose by weight) for one week | Drug: Tacrolimus capsule<br>* Twice daily dosing of tacrolimus only for a week before transplantation in this subgroup. All patients will get maintenance treatment With tacrolimus in combination With MMF and steroids after transplantation.<br>* Other names: Tac-arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| investigate the association between microbiome diversity and 12-hour mycophenolate area under the curve (AUC) | Association between microbiome diversity measures and AUC of mycophenolate for a dose interval (AUC0-tau) | 1 year | 
| investigate the association between microbiome diversity and 12-hour mycophenolate Maximum concentration (Cmax) | Association between microbiome diversity measures and Cmax of mycophenolate | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| association between microbiome diversity and 12-hour tacrolimus AUC | Association between microbiome diversity measures and AUC0-tau of tacrolimus | 1 year | 
| effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate AUC changes | Changes in microbiome diversity measures and mycophenolate AUC0-tau, with one week of mycophenolate mofetil treatment. | 1 week | 
| investigate the effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus AUC changes | Changes in microbiome diversity measures and tacrolimus AUC0-tau with one week of tacrolimus treatment | 1 week | 
| investigate if Torque Teno Virus (TTV) is a clinical useful immunometer, i.e. reflect overall immunosuppression of the recipient | Associations between TTV viral load (DNAemia) and acute rejection episodes (biopsy proven) | 1 year | 
| Association between microbiome diversity measures and Cmax of tacrolimus | Association between microbiome diversity measures and Cmax of tacrolimus | 1 year | 
| Association between microbiome diversity measures and absolute bioavailability (F) of tacrolimus | Association between microbiome diversity measures and F of tacrolimus | 1 year | 
| effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate Cmax changes | Changes in microbiome diversity measures and mycophenolate Cmax with one week of mycophenolate mofetil treatment. | 1week | 
| effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate time to Cmax (Tmax) changes | Changes in microbiome diversity measures and mycophenolate Tmax with one week of mycophenolate mofetil treatment. | 1week | 
| effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate time to terminal phase elimination rate constant (kel)changes | Changes in microbiome diversity measures and mycophenolate kel with one week of mycophenolate mofetil treatment. | 1 week | 
| effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to Cmax (Tmax) changes | Changes in microbiome diversity measures and tacrolimus Cmax with one week of tacrolimus treatment. | 1 week | 
| effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to Cmax (Tmax) changes | Changes in microbiome diversity measures and tacrolimus Tmax with one week of tacrolimus treatment. | 1 week | 
| effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to terminal phase elimination rate constant (kel) changes | Changes in microbiome diversity measures and tacrolimus kel with one week of tacrolimus treatment. | 1 week | 
| investigate if Torque Teno Virus (TTV) is a clinical useful immunometer, i.e. reflect overall immunosuppression of the recipient | Associations between TTV viral load (DNAemia) and opportunistic vial infections in need of drug treatment | 1 year | 
| investigate if Torque Teno Virus (TTV) is a clinical useful immunometer, i.e. reflect overall immunosuppression of the recipient | Associations between TTV viral load (DNAemia) and opportunistic bacterial infections requiring hospitalization | 1 year |