Evaluation of Mycophenolate Mofetil and Tacrolimus on Gut Microbiome Diversity and Pharmacokinetics in Kidney Transplant Recipients

The primary objective of this study is to investigate the association between **microbiome** diversity and 12-hour mycophenolate pharmacokinetics in patients undergoing kidney transplantation. Understanding this relationship is clinically relevant as it may influence the optimization of immunosuppressive therapy, potentially improving patient outcomes by tailoring treatment to individual microbiome profiles.

Secondary objectives include:

• Investigating the association between microbiome diversity and 12-hour tacrolimus pharmacokinetics.
• Examining the effects of mycophenolate mofetil treatment on gut microbiome changes in treatment-naïve patients and associated mycophenolate 12-hour pharmacokinetic changes.
• Assessing the effects of tacrolimus treatment on gut microbiome changes in treatment-naïve patients and associated tacrolimus 12-hour pharmacokinetic changes.
• Exploring the indirect association between microbiome diversity and immunosuppressant molecular pharmacodynamics (PD biomarkers).
• Comparing gut microbiome diversity after kidney transplantation in Norwegian and US patients.
• Investigating if TTV is a clinically useful "immunometer," reflecting overall immunosuppression of the recipient.
• Determining whether immunosuppressant molecular pharmacodynamics (cytokine responses, intracellular drug and drug target levels, and downstream mediators) can predict rejection and adverse effects.
• Integrating updated knowledge on mycophenolate and tacrolimus pharmacokinetics following renal transplantation in a combined population pharmacokinetic model for individualized dosing.
• Investigating the link between tacrolimus blood concentrations and tacrolimus-induced tremor in a PKPD model.

The clinical trial focuses on **kidney transplantation** and aims to investigate the association between microbiome diversity and 12-hour mycophenolate pharmacokinetics. The study population includes both male and female participants, with an age range that encompasses adults and older adults. Participants are not considered part of a vulnerable population. The trial specifically targets de novo, standard risk kidney transplant recipients who are scheduled to receive tacrolimus and mycophenolate mofetil as part of their immunosuppressive therapy. Only individuals undergoing their first kidney transplant, with kidneys from either deceased or living adult donors, are included. The transplantation must be ABO-compatible, with a panel reactive antibody (PRA) level of 20% or less, and participants must be donor-specific antibody (DSA) negative. The sponsor has not provided information regarding the total number of participants. Participants are required to have signed informed consent and demonstrate expected cooperation for treatment and follow-up, in accordance with ICH GCP and national/local regulations. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the association between **microbiome** diversity and the pharmacokinetics of **mycophenolate mofetil** in patients undergoing kidney transplantation. This is a Phase IV, randomized, double-blind, controlled study involving de novo, standard-risk kidney transplant recipients. Participants will receive **tacrolimus** and mycophenolate mofetil as part of their immunosuppressive therapy, with the clinical decision for this regimen being independent of the study. The trial is expected to run from October 2019 to December 2028, with a maximum treatment period of 12 months for each participant.

The study will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as first kidney transplant, ABO compatibility, and negative DSA, among others. Following the screening, participants will undergo regular follow-up visits to monitor the association between microbiome diversity and drug pharmacokinetics, as well as to assess any changes in microbiome diversity and drug exposure over time. The primary endpoint focuses on the association between microbiome diversity measures and the area under the curve (AUC0-tau) and maximum concentration (Cmax) of mycophenolate and its metabolites. Secondary endpoints include similar associations for tacrolimus, changes in pharmacokinetic parameters with one week of treatment, and the investigation of indirect associations with immunosuppressant pharmacodynamics.

Participants are expected to be involved in the study for up to 12 months, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events that necessitate discontinuation. The end-of-study visit will involve a comprehensive assessment of the primary and secondary endpoints, ensuring all data is collected for final analysis. The trial aims to provide valuable insights into the pharmacokinetic interactions between immunosuppressive drugs and the gut microbiome, potentially informing future therapeutic strategies for kidney transplant recipients.

The clinical trial involves the administration of **CellCept** 500 mg film-coated tablets, which contain the active substance **mycophenolate mofetil**. This medication is provided in the form of film-coated tablets and is administered orally. The maximum daily dose is 2000 mg, with a total maximum dose of 730 grams over a treatment period of up to 12 months. The tablets are manufactured by Roche Registration GmbH and are classified under the ATC code L04AA06, indicating their role as immunosuppressants. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Additionally, the trial includes the use of **PROGRAF** 1 mg capsules, which contain the active substance **tacrolimus**. These capsules are also administered orally and are classified as hard capsules. The maximum daily dose for tacrolimus is 30 mg, with a total maximum dose of 11 grams over a 12-month treatment period. The capsules are produced by Astellas Pharma Europe B.V. and are categorized under the ATC code L04AD02. As with the CellCept tablets, participant adherence to the dosing schedule for PROGRAF will be closely monitored to ensure compliance with the study protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this clinical trial. The primary objective of the study is to investigate the association between microbiome diversity and the pharmacokinetics of mycophenolate over a 12-hour period. The trial does not include any pediatric formulations, and both medications are of chemical origin. The study will ensure that all participants receive the correct dosages and adhere to the treatment schedule as outlined in the trial protocol.

Efficacy in this clinical trial will be assessed by evaluating the association between microbiome diversity measures and pharmacokinetic parameters of **mycophenolate mofetil** and **tacrolimus**. The primary endpoint focuses on the association between microbiome diversity and the area under the curve (AUC0-tau) and maximum concentration (Cmax) of mycophenolate and its metabolites. Secondary endpoints include similar associations for tacrolimus, as well as changes in microbiome diversity and pharmacokinetic parameters such as AUC0-tau, Cmax, time to maximum concentration (Tmax), and elimination rate constant (kel) after one week of treatment with either drug.

Additional secondary endpoints involve investigating the indirect association between microbiome diversity and immunosuppressant molecular pharmacodynamics, descriptive comparisons of microbiome diversity between populations, and associations between TTV viral load and immunosuppressive drug exposure, acute rejection episodes, and other opportunistic infections. The trial will also explore whether immunosuppressant molecular pharmacodynamics can predict rejection and adverse effects, and will assess the predictive accuracy of developed pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) models using relative predictive error (PE%) and root mean squared error (RMSE%).