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

PHASE2RECRUITING

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.

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Study details:

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 (n=45) 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 12-week period.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

1 to 18years old

SOT transplant (planned or on waiting list) excluding repeat liver transplant.

Heart OR Liver OR Renal Transplant

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.

For prospective arm, patient has had a SOT prior to receiving genotyping results.

Patient has a known hypersensitivity to tacrolimus and/or its formulation.

On a slow release preparation of Tacrolimus (e.g Advagraf extended release Brand)

Patient has a life expectancy estimated to be less than 12-weeks by the treating clinical team.

Patient and/or parent is unable to consent to the study.

Patient and/or parent is unwilling to take part in the study.

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Eligibility

Age eligible for study : 1 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-08-05

Primary completion: 2027-08-01

Study completion finish: 2027-08-02

Study type

SUPPORTIVE_CARE

Phase

PHASE2

Trial ID

NCT06529536

Intervention or treatment

DIAGNOSTIC_TEST: Genotyping for CYP3A4 and CYP3A5 genes

DEVICE: Use of NextDose platform

DRUG: Tacrolimus

Conditions

• Solid Organ Transplant

Condition: Solid Organ Transplant
DIAGNOSTIC_TEST: Genotyping for CYP3A4 and CYP3A5 genes and other drugs
Melbourne, Victoria, Australia
Sponsor: Murdoch Childrens Research Institute

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Find a site

Closest Location:

Royal Children's Hospital

Research sites nearby

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Royal Children's Hospital
Melbourne, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Prospective Cohort: Pre-emptive CYP3A5 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	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). 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.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Prospective Cohort: Pre-emptive CYP3A5 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

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).
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.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Co-primary outcome: proportion of cohort with tacrolimus concentration within therapeutic range in the initial 2 weeks post-transplant	To measure 1. Proportion of Tacrolimus doses within therapeutic range in the initial 2 weeks post-transplant. * Day 4 (assessing first dose) * Day 10 (assessing Bayesian adapted dose)	Post transplantation at Day 4 and Day 10

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Proportion of cohort to reach therapeutic range in the immediate post-transplant period.	To measure the time to therapeutic exposure in the immediate post-transplant period (first 2 weeks post transplant)	Post transplantation at Week 2
Change in proportion of cohort to stay within therapeutic range post-transplant period.	To measure the time within therapeutic range in the first 12-weeks post-transplant (as assessed at multiple time points). Timepoints: Day 1, Day 4, Day 7, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 84	Post transplantation over a 12 week period at Day 1, Day 4, Day 7, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 84.
Number of dose adjustments of tacrolimus dosing post-transplantation	To measure the number of dose adjustments of tacrolimus based on Therapeutic Drug Monitoring and/or Bayesian modelling.	Post transplantation at Week 12
Number of related adverse events in participants relating to using genotype-informed Bayesian dosing within the first 12 weeks post transplant	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.	From first dose of Tacrolimus to 12 weeks post transplantation
Number of barriers in implementing genotype-informed Bayesian dosing	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.	From first dose of Tacrolimus to 12 weeks post transplantation
Number of unfavorable clinical outcomes	To compare of the number of unfavorable clinical outcomes: rejection, donor-specific antibody formation and toxicities between the two cohorts	From first dose of Tacrolimus to 12 weeks post transplantation

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References

Clinical Trials Gov: Utilising Genotype Informed Bayesian Dosing of Tacrolimus in Children Post Solid Organ Transplantation.