Clinical trial NCT06529536: Utilising Genotype Informed Bayesian Dosing of Tacrolimus in Children Post Solid Organ Transplantation.
Official title: Genotype Informed Bayesian Dosing of Tacrolimus in Solid Organ Transplant- Pharmacogenomic Implementation in Children
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Solid Organ Transplant
Keywords: Tacrolimus
Pharmacogenomics
Bayesian
Paediatrics
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
First posted: 2024-07-31
Enrollment: 45
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a quasi-experimental trial, with a single-arm prospective intervention and retrospective comparator. Forty-five SOT recipients will be recruited from The Royal Children's Hospital Melbourne (with 45 retrospective controls taken from the immediately prior 3-5 years).

For all eligible SOT patients, a pre-emptive CYP3A5 genotype will be combined with a population PK model to predict optimal initial tacrolimus dose. In addition, genotype-informed Bayesian revised dosing will be applied to all transplant recipients over the subsequent 12-weeks post-transplant.

The prospective arm will be compared with a retrospective arm (using standard mg/kg dosing plus therapeutic drug monitoring) with primary outcome based on proportion in therapeutic range immediately post-transplant (day 4 and day 10). Finally, time within therapeutic range over the first 12-weeks post-transplant will be tested using mixed effects logistic regression.
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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) and who will be on tacrolimus as one of the main immunosuppressants post-transplant.

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.

Primary outcomes:
measure: Co-primary outcome: proportion of cohort with tacrolimus concentration within therapeutic range in the initial 2 weeks post-transplant
timeFrame: Post transplantation at Day 4 and Day 10
Secondary outcomes:
measure: Proportion of cohort to reach therapeutic range in the immediate post-transplant period.
timeFrame: Post transplantation at Week 2
measure: Change in proportion of cohort to stay within therapeutic range post-transplant period.
timeFrame: 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.
measure: Number of dose adjustments of tacrolimus dosing post-transplantation
timeFrame: Post transplantation at Week 12
measure: Number of related adverse events in participants relating to using genotype-informed Bayesian dosing within the first 12 weeks post transplant
timeFrame: From first dose of Tacrolimus to 12 weeks post transplantation
measure: Number of barriers in implementing genotype-informed Bayesian dosing
timeFrame: From first dose of Tacrolimus to 12 weeks post transplantation
measure: Number of unfavorable clinical outcomes
timeFrame: From first dose of Tacrolimus to 12 weeks post transplantation
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Royal Children's Hospital
state: Victoria
Study officials:
affiliation: Murdoch Childrens Research Institute
name: Rachel Conyers
role: PRINCIPAL_INVESTIGATOR
References: