Pharmacokinetic, Efficacy, and Tolerability Assessment of Prolonged-Release Tacrolimus in Pediatric Kidney Transplant Recipients: A Multicenter Interventional Study

The primary objective of this study is to evaluate the **bioequivalence** of tacrolimus full-area under the curve concentration between immediate-release tacrolimus (Prograf®) and prolonged-release tacrolimus (Envarsus®) in compliant pediatric kidney transplant recipients. This is clinically relevant as it aims to determine if the prolonged-release formulation can provide similar therapeutic outcomes with potentially improved adherence and reduced dosing frequency.

Secondary objectives include assessing the efficacy in terms of residual expression of NFAT-regulated genes, the potential influence of pharmacogenetics, and the pharmacodynamics of prolonged-release tacrolimus. Additionally, the study will evaluate trough levels and doses, adherence levels, cumulative dosage, signs of tacrolimus toxicity, adverse events, biopsy-proven rejections, and a decrease in estimated glomerular filtration rate (eGFR) greater than 10% from baseline, as well as the presence of donor-specific antibodies (DSAs).

The clinical trial involves **Caucasian paediatric kidney transplant recipients** as the study population. Participants are both male and female, aged between 8 and 18 years, who are currently undergoing tacrolimus (Prograf®) therapy. The trial focuses on individuals who are at least six months post-transplantation and have stable kidney function, defined by a delta eGFR of less than 10 ml/min/1.73 m² over the last three months. The study includes a vulnerable population, as it involves paediatric subjects. Participants must be able to swallow tablets with a minimum dose of 0.75 mg/day of Envarsus®. The trial does not specify the total number of participants, as the sponsor has not provided this information. Lifestyle considerations such as diet and physical activity are not detailed in the available data. Key inclusion criteria include the ability of the patient or their legal guardians to understand the study's purpose and risks, and the provision of signed informed consent. Women of childbearing potential must adhere to specific contraceptive measures or meet criteria for non-childbearing potential. The selection process for the trial population is not explicitly described in the provided data.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the pharmacokinetics, effectiveness, and tolerability of prolonged-release **tacrolimus** in Caucasian pediatric kidney transplant recipients. The trial aims to determine the bioequivalence of tacrolimus when administered as immediate-release (Prograf®) versus prolonged-release (Envarsus®) formulations, using a daily dose converting factor of 0.7. The study is set to commence on April 25, 2023, with an estimated completion date of October 31, 2025, spanning a total duration of approximately 30 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (8-18 years), stable kidney function, and the ability to swallow tablets. Following successful screening, participants will be randomized to receive either the test or comparator product. The study involves multiple follow-up visits to monitor pharmacokinetic parameters, with blood samples collected at specified intervals post-administration to calculate the full area under the curve (AUC). The primary endpoint will be analyzed using an ANOVA model on log-transformed AUC values, with secondary endpoints assessed through descriptive statistics.

The expected length of participant involvement is up to four weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent by the participant or their legal guardians. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to ensure safety and gather any remaining data. The trial is conducted under strict adherence to ethical guidelines, with informed consent obtained from all participants and their guardians prior to enrollment.

The clinical trial involves the administration of **tacrolimus** in various formulations to assess its pharmacokinetics, effectiveness, and tolerability in pediatric kidney transplantation. The experimental medication, Envarsus, is available in prolonged-release tablet form with dosages of 0.75 mg, 1 mg, and 4 mg. The tablets are administered orally once daily, with a maximum daily dose of 4 mg and a total dose not exceeding 112 mg over a treatment period of 4 weeks. The active substance, tacrolimus, is of chemical origin and is used for immunosuppression. The manufacturer of Envarsus is Chiesi Farmaceutici S.P.A., and the product is authorized for use in the European Union.

The comparator treatment in the study is Prograf, which is also based on the active substance **tacrolimus**. Prograf is provided in hard capsule form with dosages of 0.5 mg, 1 mg, and 5 mg. The capsules are administered orally, with a maximum daily dose of 10 mg and a total dose not exceeding 280 mg over the same 4-week treatment period. The manufacturer of Prograf is Astellas Pharma GmbH, and the product is authorized for use in Germany. Both Envarsus and Prograf are used for immunosuppression in the context of this clinical trial.

Participant compliance with the dosing schedule is monitored through blood samples collected at specified intervals post-administration to ensure adherence to the protocol. The study aims to determine the bioequivalence of the prolonged-release formulation of tacrolimus (Envarsus) compared to the immediate-release formulation (Prograf) using a daily dose converting factor of 0.7. The trial does not involve any orphan drug designations or pediatric formulations.

The efficacy of the clinical trial will be assessed by evaluating the pharmacokinetics and pharmacodynamics of prolonged-release **tacrolimus** in pediatric kidney transplant recipients. The primary endpoint involves the analysis of the full area under the curve (AUC) for **tacrolimus** concentrations. Blood samples will be collected at specific time points: before administration and at 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, and 24 hours post-administration. The AUC values will be compared between immediate-release **tacrolimus** (Prograf®) and prolonged-release **tacrolimus** (Envarsus®) using an ANOVA model on log-transformed AUC values. The analysis will include sequence, subject within sequence, and period as fixed factors, with the 90% confidence interval required to fall within the acceptance boundaries of 0.8 and 1.25.

Secondary endpoints will be assessed using descriptive statistics, including absolute and relative frequencies, median and interquartile range, geometric mean, arithmetic mean, standard deviation, minimum and maximum, and coefficients of variation. The suitability of limited sampling strategies (LSS) for 24-hour AUC calculation will be evaluated using Pearson’s correlation coefficients. These analyses aim to compare the pharmacokinetic and pharmacodynamic profiles of both phases of the trial, providing a comprehensive assessment of the efficacy of prolonged-release **tacrolimus** in the specified patient population.