Utilising Genotype Informed Bayesian Dosing of Tacrolimus in Children Post Solid Organ Transplantation. (BRUNO-PIC)

Genotype Informed Bayesian Dosing of Tacrolimus in Solid Organ Transplant- Pharmacogenomic Implementation in Children

This study aims to evaluate the efficacy of genotype-informed Bayesian dosing of tacrolimus in optimising drug exposure among paediatric solid organ transplant recipients. By tailoring tacrolimus dosage based on individual genetic makeup and using Bayesian modeling to predict drug levels, the researchers hope to increase the likelihood of achieving therapeutic drug concentrations while minimising the risk of adverse events associated with subtherapeutic or supratherapeutic exposure.

Study Overview

• Status: Recruiting
• Conditions: Solid Organ Transplant
• Intervention / Treatment: Device: Use of NextDose platform; Diagnostic test: Genotyping for CYP3A4 and CYP3A5 genes; Drug: Tacrolimus

Detailed Description

Tacrolimus, a calcineurin inhibitor is an effective immunosuppressant for solid organ transplants (SOT). Due to its narrow therapeutic index and individual variability in its pharmacokinetics (PK), this can lead to inefficacy, toxicities and suboptimal outcomes.

Tacrolimus is typically administered orally twice daily, with a starting dose scaled linearly to body weight (mg/kg). Dose is then adjusted based on measured steady-state trough (pre-dose) whole blood tacrolimus concentrations, to bring to within a desired "therapeutic range". However, this dosing strategy remains associated with incomplete effectiveness and toxicities in a substantial proportion of recipients, related to under- or over-exposure respectively.

Cytochrome P450 CYP3A4 and CYP3A5 enzymes metabolise tacrolimus, with research suggesting a link between genetic variants for these isoenzymes and achievement of tacrolimus target levels. Genotyping for the CYP3A5 & CYP3A4 gene prior to SOT can identify individuals who are at risk of high or low tacrolimus levels, and guide tacrolimus dosing prior to transplantation. Bayesian prediction is a pharmaco-statistical technique that uses population pharmacokinetic data and individual patient characteristics to accurately predict the tacrolimus dose required to achieve a target concentration. Subtherapeutic levels post-transplant, increases the risk of acute rejection. Furthermore, failure to maintain the target tacrolimus range for the first 6 months significantly raises the chance of rejection, donor-specific antibody formation and graft loss.

Genotype informed dosing algorithms may optimise and ameliorate sub-therapeutic levels, thus potentially reducing the risk of rejection or toxicity, with subsequent Bayesian dosing increasing time within the range of safe and effective concentrations in the subsequent weeks (as shown in adult kidney transplant recipients).

To determine if implementing a genotype-informed Bayesian dosing of tacrolimus is superior to standard weight-based dosing and empiric dose adjustment to trough concentrations post SOT, a combined retrospective/prospective cohort study in Solid Organ Transplant recipients will be undertaken at The Royal Children's Hospital Melbourne.

The outcomes from the Retrospective cohort (over a 5-year period) using clinician-led therapeutic drug monitoring will be compared with the Prospective cohort (n=45), using genotype to predict initial tacrolimus doses and predictive Bayesian dosing for ongoing tacrolimus dosing over a 8-week period.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Rachel Conyers; Phone Number: 03 9936 6770; Email: pharmaco.genomics@mcri.edu.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Recruiting
      • Royal Children's Hospital
      • Principal Investigator: A/Prof Rachel Conyers
      • Contact: Dhrita Khatri; Phone Number: 03 9936 6087; Email: pharmaco.genomics@mcri.edu.au
      • Contact: David Metz; Phone Number: 03 9345 5533; Email: david.metz@rch.org.au
      • Principal Investigator: A/Prof David Metz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Participants will be assigned to the prospective arm if treated at Royal Children's Hospital who are receiving a solid organ transplant (SOT) (excluding repeat graft in liver transplant recipients, or lung or intestinal transplant) and who will be on tacrolimus as one of the main immunosuppressants post-transplant.

Inclusion Criteria:

• Age 1-18 years of age
• Kidney, liver or heart transplant recipients
• Participant and/or parent consent to the study (prospective arm only)

Exclusion Criteria:

• Previous liver transplant.
• Lung OR Intestinal transplant.
• Insufficient time before transplant for pharmacogenomic analysis (prospective arm only)
• Immunosuppressant regimen not containing tacrolimus immediate release product
• Known hypersensitivity to tacrolimus and/or its formulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction; Planned SOT recipients where initial tacrolimus dosing will be based on genotype and subsequent doses predicted using Bayesian revised dosing using NextDose. NextDose, a web-based tool is a model-informed precision dosing software tool used to optimise dosage regimens. It uses Bayesian statistics to integrate prior drug information from a population pharmacokinetic (popPK) model, individual characteristics, and drug concentrations to provide the most accurate individual pharmacokinetic (PK) estimates. The popPK model, a mathematical-statistical model developed from real patient data, captures the drug's typical pharmacokinetics, its variability among individuals and over time, and the factors influencing this variability. By leveraging prior knowledge about a drug's PK along with individual patient data and drug concentrations, the software accurately estimates individual PK parameters with minimal drug concentration data. Tacrolimus dose, form, frequency, & duration will be assessed

Device: Use of NextDose platform; NextDose platform is a forecasting tool used to predict tacrolimus dosage. It is a freely available tool and will be used in accordance with guideline. The dosing recommendations will be led by the academic pharmacist in consultation with the PI. This tool will use genotype-informed Bayesian dosing to help predict the time course of tacrolimus concentrations in the body.; Diagnostic test: Genotyping for CYP3A4 and CYP3A5 genes; Genotyping: Patients in the prospective (intervention) arm will undergo genotyping using Illumina's genome-wide genotyping array (Infinium Global Screening Array). Pre-transplant genotyping will test for CYP3A5 *3, *6, *7, *8 and *9 alleles, and will test for CYP3A4*22 only (with CYP3A4*1 reported if no variant corresponding to *22 was present). The determined diplotypes for CYP3A5 will be matched with predicted phenotypes using the Clinical Pharmacogenetics Implementation Consortium (CPIC®) proposed genotype-to-phenotype translation table. The assignment of the phenotype is outlined in the CPIC guidelines which will used to predict initial dose of tacrolimus. In addition, influence of CYP3A4 will be incorporated based on recent literature and interventional trials. Initial dose in BRUNO-PIC will use allometric size scaling from adult dose, with adjustment based on genotype (CYP3A4 & CYP3A5); Drug: Tacrolimus; Tacrolimus is administered to all patients post SOT at The Royal Children's Hospital (RCH); Other Names: Prograf (Brand)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with tacrolimus concentration within the acceptable range (80-125% of concentration target, Cssavg) on post-transplant dosing day 4 (DD4), Week 3 and Week 8	To measure the proportion of cohort with tacrolimus concentration within 80-125% of concentration target on post-transplant dosing day 4 (DD4), week 3 and week 8 - within 80-125% of Cssavg target (where Cssavg is the average steady state concentration).	Post transplantation at Day 4, Week 3 and week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time taken to reach target tacrolimus concentrations post-transplant.	Median time to acceptable range (80-125% Cssavg) in the immediate post-transplant period.	Post transplantation through first 8-week period
Time with tacrolimus concentrations within the acceptable range over the first 8 weeks post-transplantation.	Time within acceptable range (80-125% of Cssavg) over the first 8 weeks post-transplant	Post transplantation through first 8-week period
Proportion of participants with acceptable trough tacrolimus concentrations immediately post-transplant (day 4).	Proportion of tacrolimus concentrations within 80-125% of Csstrough target (steady-state trough concentrations) on DD4	Post transplantation at Day 4
Number of tacrolimus dose adjustments made over the first 8 weeks post transplant.	Number of dose adjustments of tacrolimus based on therapeutic window approach (TWA) and/or Bayesian.	Post transplantation at Week 8
Safety of genotype-informed Bayesian dosing within the first 8 weeks post transplant	Safety of genotype-informed Bayesian dosing, including description of number of clinical outcomes: rejection, donor-specific antibody formation; tacrolimus toxicities of new onset diabetes after transplantation.	From first dose of Tacrolimus through to 8 weeks post transplantation
Feasibility of genotype-informed Bayesian dosing and barriers to implementation.	To record any barriers or challenges that occur in using genotyping and Bayesian dosing for dose prediction of tacrolimus. These can include any technical failures of the NextDose platform for dosing predictions or data access.	From first dose of Tacrolimus through to 8 weeks post transplantation

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Investigators: Principal Investigator: Rachel Conyers, Murdoch Childrens Research Institute; Principal Investigator: David Metz, MBBS, PhD, Murdoch Childrens Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2024
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 2, 2027

Study Registration Dates

• First Submitted: July 26, 2024
• First Submitted That Met QC Criteria: July 26, 2024
• First Posted (Actual): July 31, 2024

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 22, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Tacrolimus; Pharmacogenomics; Bayesian; Paediatrics
• Additional Relevant MeSH Terms: Organic Chemicals; Macrolides; Lactones; Genetic Phenomena; Tacrolimus; Genotype
• Other Study ID Numbers: 2023/ETH02699

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The de-identified data set collected for this analysis of this study will be available six months after publication of the primary outcome. The study protocol and analysis plan will also be available. The data must be obtained from the Murdoch Children's Research Institute. Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties, the Study Management Group must see and approve the data analysis plan describing how the data will be analysed, there must be an agreement around appropriate acknowledgment and any additional costs involved must be covered. Should the Study Management Group be unavailable, this role is delegated to the Murdoch Children's Research Institute. Data will only be shared with a recognized research organisation which has approved the proposed analysis plan.
• IPD Sharing Time Frame: 6 months after publication of primary outcome
• IPD Sharing Access Criteria: Data access agreement;; approval by Trial Steering Committee;; recognized research institutions.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No