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

IntroductionTacrolimus 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 analysisBRUNO-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 disseminationThe ethics approval of the trial has been obtained from the Sydney Childrens Ethics Committee (2023/ETH02699). Findings will be disseminated through peer-reviewed publications and professional conference presentations. Trial registrationClinicalTrials.gov NCT 06529536 STRENGTHS AND LIMITATIONS OF THIS STUDYO_ST_ABSStrengthsC_ST_ABSThis is a prospective study in paediatric solid organ transplant recipients combining (a) pre-transplant CYP3A5/3A4 genotyping to improve initial tacrolimus dose, and (b) post-transplant Bayesian individualised tacrolimus dosing to increase time within the safe and effective range. Use of a target concentration approach based on average steady state concentrations is expected to increase exposure in individuals with low tacrolimus clearance and reduce overexposure in individuals with high tacrolimus clearance (e.g. CYP3A5 expressors). LimitationsThe lack of a randomised comparator arm in this prospective interventional trial precludes unconfounded determination of superiority over standard care. The intervention may not be generalisable to other transplant recipients (e.g. lung, intestinal, hematopoietic stem cell transplant). ADMINISTRATIVE INFORMATIONO_ST_ABSProtocol VersionC_ST_ABSThis trial is approved Sydney Childrens Ethics Committee (2023/ETH02699). The study is currently version 4, 26.05.2025 (Supplementary File 2) FundingBRUNO-PIC is funded by the 2023 Medical Research Future Fund - Genomics Health Future Mission (MARVEL-PIC (MRF/2024900). This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. SponsorshipMurdoch Childrens Research Institute