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

Phase 2

Recruiting

• Conditions: Solid Organ Transplant
• Interventions: Diagnostic Test: Genotyping for CYP3A4 and CYP3A5 genes; Device: Use of NextDose platform; Drug: Tacrolimus

• Registration Number: NCT06529536
• Lead Sponsor: Murdoch Childrens Research Institute

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.

Study Timeline

• Study First Submitted: 2024-07-26
• Study First Submitted QC: 2024-07-26
• Study First Posted: 2024-07-31
• Study Start: 2024-08-05
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-11
• Last Update Posted: 2025-09-17
• Primary Completion: 2027-08
• Study Completion: 2027-08-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 45

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction	Genotyping for CYP3A4 and CYP3A5 genes	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
Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction	Use of NextDose platform	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
Prospective Cohort: Pre-emptive CYP3A5/3A4 genotype combined with a Bayesian dose prediction	Tacrolimus	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

Primary Outcome Measures

Name	Time	Method
Primary outcome: Proportion of cohort with tacrolimus concentration within 80-125% of concentration target (Cssavg: average steady state concentration) on post-transplant dosing day 4 (DD4), Week 3 and Week 8	Post transplantation at Day 4, 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 (average steady state concentration) is calculated using Bayesian maximum a posteriori estimation, from observed concentrations and clinical covariates)

Secondary Outcome Measures

Name	Time	Method
Proportion of cohort reaching acceptable concentrations.	Post transplantation through first 8-week period	To measure the median time to acceptable range (80-125% Cssavg, steady state concentration) in the immediate post-transplant period.
Change in proportion of cohort to stay within acceptable range post-transplant period.	Post transplantation through first 8-week period	To measure the time within acceptable range(80-125% of Cssavg, steady state concentration) in the first 8-weeks post-transplant
Change in proportion of cohort to stay within acceptable range immediately post-transplant.	Post transplantation at Day 4	To measure the proportion of tacrolimus concentrations within 80-125% of Csstrough (steady state concentration) target on DD4
Number of dose adjustments of tacrolimus dosing post-transplantation	Post transplantation at Week 8	To measure the number of dose adjustments of tacrolimus based on Therapeutic Drug Monitoring and/or Bayesian modelling.
Number of related adverse events in participants relating to using genotype-informed Bayesian dosing within the first 8 weeks post transplant	From first dose of Tacrolimus through to 8 weeks post transplantation	To record any adverse events that occur relating to using genotyping and Bayesian dosing for dose prediction of tacrolimus. These include any subtherapeutic or supratherapeutic tacrolimus levels as a direct result of genotyping or Bayesian prediction.
Number of barriers in implementing genotype-informed Bayesian dosing	From first dose of Tacrolimus through to 8 weeks post transplantation	To record any barriers 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.
Number of unfavorable clinical outcomes	From first dose of Tacrolimus to 8 weeks post transplantation	To compare of the number of unfavorable clinical outcomes: rejection, donor-specific antibody formation and toxicities between the two cohorts

Trial Locations

Locations (1)

Royal Children's Hospital; 🇦🇺 Melbourne, Victoria, Australia