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

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.

• Time taken to reach target tacrolimus concentrations post-transplant. [Срок оценки: Post transplantation through first 8-week period]
• Time with tacrolimus concentrations within the acceptable range over the first 8 weeks post-transplantation. [Срок оценки: Post transplantation through first 8-week period]
• Proportion of participants with acceptable trough tacrolimus concentrations immediately post-transplant (day 4). [Срок оценки: Post transplantation at Day 4]
• Number of tacrolimus dose adjustments made over the first 8 weeks post transplant. [Срок оценки: Post transplantation at Week 8]
• Safety of genotype-informed Bayesian dosing within the first 8 weeks post transplant [Срок оценки: From first dose of Tacrolimus through to 8 weeks post transplantation]
• Feasibility of genotype-informed Bayesian dosing and barriers to implementation. [Срок оценки: From first dose of Tacrolimus through to 8 weeks post transplantation]