Utilising Genotype Informed Bayesian Dosing of Tacrolimus in Children Post Solid Organ Transplantation.

NCT06529536 | Recruiting Phase 4 DMC

• 1 other identifier: 2023/ETH02699
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Solid Organ Transplant

Keywords

Tacrolimus; Pharmacogenomics; Bayesian; Paediatrics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Time taken to reach target tacrolimus concentrations post-transplant.

  Post transplantation through first 8-week period

• Time with tacrolimus concentrations within the acceptable range over the first 8 weeks post-transplantation.

  Post transplantation through first 8-week period

• Proportion of participants with acceptable trough tacrolimus concentrations immediately post-transplant (day 4).

  Post transplantation at Day 4

• Number of tacrolimus dose adjustments made over the first 8 weeks post transplant.

  Post transplantation at Week 8

• Safety of genotype-informed Bayesian dosing within the first 8 weeks post transplant

  From first dose of Tacrolimus through to 8 weeks post transplantation

Study Arms (1)

Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction

EXPERIMENTAL

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

Diagnostic Test: Genotyping for CYP3A4 and CYP3A5 genes; Device: Use of NextDose platform; Drug: Tacrolimus

Interventions

Use of NextDose platform DEVICE

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.

Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction

Tacrolimus DRUG

Tacrolimus is administered to all patients post SOT at The Royal Children's Hospital (RCH)

Also known as: Prograf (Brand)

Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction

Genotyping for CYP3A4 and CYP3A5 genes DIAGNOSTIC_TEST

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)

Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Murdoch Childrens Research Institute: lead

Study Sites (1)

Royal Children's Hospital

Melbourne, Victoria, 3052, Australia

RECRUITING

MeSH Terms

Interventions

Genotype; Tacrolimus

Intervention Hierarchy (Ancestors)

Genetic Phenomena; Macrolides; Lactones; Organic Chemicals

Study Officials

• Rachel Conyers

  Murdoch Childrens Research Institute

  PRINCIPAL INVESTIGATOR

• David Metz, MBBS, PhD

  Murdoch Childrens Research Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rachel Conyers

CONTACT

03 9936 6770; pharmaco.genomics@mcri.edu.au

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open-label trial with a prospective intervention arm and a retrospective standard of care comparator arm. Forty-five SOT recipients will be recruited from The Royal Children's Hospital Melbourne (with retrospective controls taken from the immediately prior 5 years). For all eligible SOT patients, a pre-emptive CYP3A5 and CYP3A4 genotype will be combined with a population PK model to predict optimal initial tacrolimus dose. In addition, genotype-informed Bayesian revised dosing will be applied to all transplant recipients over the subsequent 8-weeks post-transplant. The prospective arm will be compared with a retrospective arm (using standard mg/kg dosing plus therapeutic drug monitoring) where the primary outcome is the proportion of participants in each cohort with tacrolimus concentration (steady-state average concentration) within 80-125% of concentration target (Cssavg) on post-transplant dosing DD4, Week 3 \& Week 8.

Study Record Dates

• First Submitted: July 26, 2024
• First Posted: July 31, 2024
• Study Start: August 5, 2024
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 2, 2027
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 6 months after publication of primary outcome
• Access Criteria: 1. Data access agreement; 2. approval by Trial Steering Committee; 3. recognized research institutions.

Locations

AU (1)