Utilising Genotype Informed Bayesian Dosing of Tacrolimus in Children Post Solid Organ Transplantation.
- Conditions
- Solid Organ Transplant
- Interventions
- Diagnostic Test: Genotyping for CYP3A4 and CYP3A5 genesDevice: Use of NextDose platform
- 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 (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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 45
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Prospective Cohort: Pre-emptive CYP3A5 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 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 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 Co-primary outcome: proportion of cohort with tacrolimus concentration within therapeutic range in the initial 2 weeks post-transplant Post transplantation at Day 4 and Day 10 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)
- Secondary Outcome Measures
Name Time Method Number of dose adjustments of tacrolimus dosing post-transplantation Post transplantation at Week 12 To measure the number of dose adjustments of tacrolimus based on Therapeutic Drug Monitoring and/or Bayesian modelling.
Proportion of cohort to reach therapeutic range in the immediate post-transplant period. Post transplantation at Week 2 To measure the time to therapeutic exposure in the immediate post-transplant period (first 2 weeks post transplant)
Change in proportion of cohort to stay within therapeutic range post-transplant period. 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. 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
Number of related adverse events in participants relating to using genotype-informed Bayesian dosing within the first 12 weeks post transplant From first dose of Tacrolimus to 12 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 unfavorable clinical outcomes From first dose of Tacrolimus to 12 weeks post transplantation To compare of the number of unfavorable clinical outcomes: rejection, donor-specific antibody formation and toxicities between the two cohorts
Number of barriers in implementing genotype-informed Bayesian dosing From first dose of Tacrolimus to 12 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.
Trial Locations
- Locations (1)
Royal Children's Hospital
🇦🇺Melbourne, Victoria, Australia