Protocol for Bayesian combined multi-genotype and concentration informed tacrolimus dosing in paediatric solid organ transplantation (BRUNO-PIC)

Introduction

Tacrolimus is an immunosuppressant used extensively in solid organ transplantation. Whilst highly effective in preventing organ rejection, it has a narrow range of safe and effective concentrations and wide pharmacokinetic variability, which can lead to and suboptimal outcomes or unacceptable toxicities. Importantly, much is known about the sources of pharmacokinetic variability. There is a clear link between body size, pharmacogenetic variants of cytochrome P450 (CYP) 3A4 and CYP3A5 and typical dose requirement. Increasing individualisation of initial dose is expected to increase the proportion of transplant recipients with tacrolimus concentrations within the acceptable range in the initial post-transplant week. Subsequently, maximum a posteriori Bayesian dosing can better maintain concentrations within the acceptable range over time. Together, this should lead to improved patient outcomes.

Method and analysis

BRUNO-PIC is an open-label trial with a prospective intervention arm and a retrospective standard of care comparator arm. The prospective arm evaluates covariate informed initial dosing combined with Bayesian dose adjustment in children undergoing kidney, liver or heart transplant. CYP3A5 and CYP3A4 genotyping will be combined with allometric size scaling to predict initial tacrolimus dose. Post-transplant dose adjustment will be guided by NextDose, a Bayesian dosing platform that incorporates genotype, clinical characteristics, measured tacrolimus concentrations and a population pharmacokinetic (popPK) model to inform initial dosing and guide dose adjustments following transplant. The primary objective of this study is to determine whether genotype-informed Bayesian dosing of tacrolimus leads to better achievement of tacrolimus concentrations within the acceptable range over the first 8 weeks post-transplant in paediatric solid organ transplant (SOT) recipients (kidney, heart and liver), when compared to a retrospective historical control group using standard of care dosing. The primary outcome is the proportion of each cohort with tacrolimus concentration (steady-state average concentration) within the acceptable range of 80-125% of target at post-transplant dosing day 4 (DD4), at week 3 and at week 8. Secondary outcomes include the proportion with trough concentration within the acceptable range on DD4, the median time to acceptable range, and the time within acceptable range over the first 8-weeks post-transplant.

Ethics and dissemination

The ethics approval of the trial has been obtained from the Sydney Children’s Ethics Committee (2023/ETH02699). Findings will be disseminated through peer-reviewed publications and professional conference presentations.

Trial registration

ClinicalTrials.gov NCT 06529536

STRENGTHS AND LIMITATIONS OF THIS STUDY

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