Bioequivalence Study of Tacrolimus and Mycophenolate Mofetil in Kidney Transplant Recipients at Steady-State

The primary objective of this study is to **assess oral bioequivalence** of generic tacrolimus (Tac) and mycophenolate mofetil (MMF) in kidney transplant recipients at steady-state. This evaluation is clinically significant as it ensures that generic formulations provide the same therapeutic effects as their branded counterparts, which is crucial for maintaining the efficacy and safety of immunosuppressive therapy in organ transplantation.

Secondary objectives include:

• Investigating the direct and indirect effects of gut microbiota on Tac and MMF pharmacokinetics. Understanding these effects can help optimize dosing regimens and improve patient outcomes by accounting for individual variations in drug metabolism.
• Updating current population pharmacokinetic models by including data on generic products, if bioequivalent. This will enhance the precision of pharmacokinetic predictions and support the safe and effective use of generic immunosuppressants in clinical practice.

The clinical trial involves participants who are **kidney transplant** recipients, with the primary objective of assessing the oral bioequivalence of generic Tac and MMF in these individuals at a steady-state. The study population includes both male and female subjects, aged 18 years and older, who are on a stable immunosuppressive therapy regimen. Participants are required to be on a specific immunosuppressive drug regimen containing Prograf® (tacrolimus twice daily) and CellCept® (mycophenolate mofetil twice daily). They must be capable of complying with medical treatment independently and have provided signed informed consent. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to assess the **oral bioequivalence** of generic tacrolimus and mycophenolate mofetil in kidney transplant recipients at a steady state. This is a **randomized**, **double-blind**, and **controlled** trial, categorized as a Phase IV, low-intervention study. The trial will involve the administration of the investigational products, Tacrolimus Ascend 1 mg hard capsules and Mycophenolate Mofetil Accord 250 mg capsules, compared against the reference products, Prograf 1 mg capsules and CellCept 500 mg film-coated tablets. The trial is expected to commence recruitment on August 18, 2025, and conclude by December 31, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being a kidney transplant recipient on stable immunosuppressive therapy, aged above 18, and able to comply with medical treatment independently. Following the screening, participants will be randomized to receive either the test or reference products. The primary endpoint will measure the **AUC0-12** and **Cmax** of tacrolimus and mycophenolic acid, adhering to EMA bioequivalence guidelines. Secondary endpoints will include additional pharmacokinetic parameters and variables.

The trial will involve multiple follow-up visits to monitor the pharmacokinetic parameters and ensure participant safety. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to two months, aligning with the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is structured to minimize participant burden, with many samples being self-collected at home through finger-prick methods.

The clinical trial involves the administration of several **experimental medications** to assess their bioequivalence in kidney transplant recipients. The first experimental medication is **Tacrolimus Ascend 1 mg Hartkapseln**, which is a hard capsule containing the active substance **tacrolimus**. This medication is administered orally with a maximum daily dose of 30 mg and a total maximum dose of 420 mg over a treatment period of 2 weeks. The pharmaceutical form is a hard capsule, and the medication is produced by Ascend GmbH. Participant compliance is monitored to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **Mycophenolate Mofetil Accord 250 mg kapselit**, which is also in the form of a hard capsule. The active substance is **mycophenolate mofetil**, and it is administered orally. The maximum daily dose is 3 g, with a total maximum dose of 42 g over a 2-week treatment period. This medication is manufactured by Accord Healthcare B.V. Compliance with the dosing regimen is closely monitored throughout the trial.

The trial also includes the administration of **PROGRAF 1 mg capsule**, which contains the active substance **tacrolimus**. This medication is provided in a hard capsule form and is administered orally. The maximum daily dose is 40 mg, with a total maximum dose of 500 mg over a 2-week treatment period. Astellas Pharma Europe B.V. is the manufacturer of this medication. Participant adherence to the dosing schedule is ensured through regular monitoring.

Additionally, the trial utilizes **CellCept 500 mg film-coated tablets** as a comparator treatment. The active substance in this medication is **mycophenolate mofetil**, and it is administered orally in the form of film-coated tablets. The maximum daily dose is 3 g, with a total maximum dose of 45 g over a 2-week treatment period. This medication is produced by Roche Registration GmbH. Compliance with the dosing schedule is monitored to ensure accurate assessment of bioequivalence.

The efficacy of the clinical trial will be assessed by evaluating the **bioequivalence** of generic tacrolimus (Tac) and mycophenolate mofetil (MMF) in kidney transplant recipients. The primary endpoints for efficacy assessment include the area under the concentration-time curve from 0 to 12 hours (AUC0-12) and the maximum concentration (Cmax) of Tac and mycophenolic acid (MPA), as per the European Medicines Agency (EMA) bioequivalence guidelines. Secondary endpoints will involve additional pharmacokinetic parameters and variables such as AUC0-12, Cmax, trough concentration (C0), concentration at 12 hours (C12), apparent clearance (CL/F), population pharmacokinetic (popPK) model parameters, metagenomic feces analyses, and feces-derived ex vivo drug conversion rates.

The measurement and collection of these parameters will be conducted at steady-state conditions in the participants. The trial is designed to ensure that the medicinal products are used in accordance with their marketing authorization, and the decision to treat patients with the original medicinal products is made by the treating physician. The trial is categorized as a Phase IV, low-intervention clinical trial, with minimal extra burden on patients due to the extended blood sampling, which includes finger-prick samples that can be self-administered at home.