Genotype Informed Bayesian Dosing of Tacrolimus in Solid Organ Transplant- Pharmacogenomic Implementation in Children
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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 genetic variants for these isoenzymes and achievement of tacrolimus target levels. Genotyping for the CYP3A5 & CYP3A4 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, with subsequent Bayesian dosing increasing time within the range of safe and effective concentrations in the subsequent weeks (as shown in adult kidney transplant recipients).
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants will be assigned to the prospective arm if treated at Royal Children's Hospital who are receiving a solid organ transplant (SOT) (excluding repeat graft in liver transplant recipients, or lung or intestinal transplant) and who will be on tacrolimus as one of the main immunosuppressants post-transplant.
- •Inclusion Criteria:
- •Age 1-18 years of age
- •Kidney, liver or heart transplant recipients
- •Participant and/or parent consent to the study (prospective arm only)
排除标准
- •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.
研究组 & 干预措施
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
干预措施: Genotyping for CYP3A4 and CYP3A5 genes (Diagnostic Test)
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
干预措施: Use of NextDose platform (Device)
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
干预措施: Tacrolimus (Drug)
结局指标
主要结局
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
时间窗: 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 is the average steady state concentration).
次要结局
- 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)
- Feasibility of genotype-informed Bayesian dosing and barriers to implementation.(From first dose of Tacrolimus through to 8 weeks post transplantation)