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

NCT ID: NCT06529536

Last Updated: 2025-09-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-08-05
• Study Completion Date: 2027-08-02

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.

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 the CYP3A5 genetic makeup and achieving tacrolimus target levels. Genotyping for the CYP3A5 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.

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.

Conditions

Solid Organ Transplant

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Genotyping for CYP3A4 and CYP3A5 genes

Intervention Type: 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)

Use of NextDose platform

Intervention Type: 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.

Tacrolimus

Intervention Type: DRUG

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

Interventions

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)

Intervention Type: DIAGNOSTIC_TEST

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.

Intervention Type: DEVICE

Tacrolimus

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

Intervention Type: DRUG

Other Intervention Names

Prograf (Brand)

Eligibility Criteria

Inclusion Criteria

• 1 to 18years old
• SOT transplant (planned or on waiting list).
• Heart OR Liver OR Renal transplant recipients
• Amenable to venepuncture and blood draw
• Patient and/or parent consented to the study.

Exclusion Criteria

• older than 18 year old
• younger than 1 year old
• Previous liver transplant.
• Lung OR Intestinal transplant.
• Insufficient time before transplant for pharmacogenomic analysis (prospective arm only)
• Patient has a known hypersensitivity to tacrolimus and/or its formulation.
• On a slow release preparation of Tacrolimus (e.g Advagraf extended release Brand)
• Immunosuppressant regimen not containing tacrolimus immediate release product
• Patient and/or parent is unable to consent to the study.
• Patient and/or parent is unwilling to take part in the study.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Murdoch Childrens Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rachel Conyers

Role: PRINCIPAL_INVESTIGATOR

Murdoch Childrens Research Institute

Locations

Royal Children's Hospital

Melbourne, Victoria, Australia

Site Status: RECRUITING

Countries

Australia

Central Contacts

Rachel Conyers

Role: CONTACT

pharmaco.genomics@mcri.edu.au

03 9936 6770

Facility Contacts

Dhrita Khatri

Role: primary

pharmaco.genomics@mcri.edu.au

03 9936 6087

David Metz

Role: backup

david.metz@rch.org.au

03 9345 5533

Other Identifiers

2023/ETH02699

Identifier Type: -

Identifier Source: org_study_id