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.

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.

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.

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)

Exclusion Criteria:

• 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.

The de-identified data set collected for this analysis of this study will be available six months after publication of the primary outcome. The study protocol and analysis plan will also be available. The data must be obtained from the Murdoch Children's Research Institute. Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties, the Study Management Group must see and approve the data analysis plan describing how the data will be analysed, there must be an agreement around appropriate acknowledgment and any additional costs involved must be covered. Should the Study Management Group be unavailable, this role is delegated to the Murdoch Children's Research Institute. Data will only be shared with a recognized research organisation which has approved the proposed analysis plan.

6 months after publication of primary outcome

1. Data access agreement;
2. approval by Trial Steering Committee;
3. recognized research institutions.