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 incomplete effectiveness, toxicities and suboptimal outcomes. Yet much is known about this pharmacokinetic variability. Tacrolimus is metabolised by cytochrome P450 (CYP) 3A4 and CYP3A5, with a clear link between pharmacogenetic variants and dose requirement. With additional patient covariates, more than 40% of tacrolimus’ pharmacokinetic variability can be explained. Individualisation of initial dose can increase proportion of transplant recipients within the acceptable range of concentrations in the initial post-transplant week, and subsequent maximum a posteriori Bayesian dosing can increase time in acceptable range over time, with potential to improve 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 doses followed by Bayesian dose adjustment in children undergoing kidney, liver or heart transplant. A CYP3A5 and CYP3A4 genotype will be combined with allometric size scaling to predict initial tacrolimus doses. 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 model to maximally inform initial doses and dose adjustment recommendations over the first 8-weeks post-transplant. The co-primary outcome is the proportion of cohort with measured tacrolimus concentration within 80-125% of target, at post-transplant dosing day 4 (Ctrough), and day 4 at week 3 and week 8 (Cavgss target) post-transplant. The secondary outcomes include median time to acceptable range and the time in the 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