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.
Age 1-18 years of age
Kidney, liver or heart transplant recipients
Participant and/or parent consent to the study (prospective arm only)
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
Single group
Genotyping for CYP3A4 and CYP3A5 genes
Diagnostic testGenotyping: Patients in the prospective (intervention) arm will undergo genotyping using Illumina's genome-wide genotyping array (Infinium Global Screening Array). Pre-transplant genotyping will test for CYP3A5 \*3, \*6, \*7, \*8 and \*9 alleles, and will test for CYP3A4\*22 only (with CYP3A4\*1 reported if no variant corresponding to \*22 was present). The determined diplotypes for CYP3A5 will be matched with predicted phenotypes using the Clinical Pharmacogenetics Implementation Consortium (CPIC®) proposed genotype-to-phenotype translation table. The assignment of the phenotype is outlined in the CPIC guidelines which will used to predict initial dose of tacrolimus. In addition, influence of CYP3A4 will be incorporated based on recent literature and interventional trials. Initial dose in BRUNO-PIC will use allometric size scaling from adult dose, with adjustment based on genotype (CYP3A4 \& CYP3A5)
Use of NextDose platform
DeviceNextDose platform is a forecasting tool used to predict tacrolimus dosage. It is a freely available tool and will be used in accordance with guideline. The dosing recommendations will be led by the academic pharmacist in consultation with the PI. This tool will use genotype-informed Bayesian dosing to help predict the time course of tacrolimus concentrations in the body.
Tacrolimus
DrugTacrolimus is administered to all patients post SOT at The Royal Children's Hospital (RCH)
Proportion of participants with tacrolimus concentration within the acceptable range (80-125% of concentration target, Cssavg) on post-transplant dosing day 4 (DD4), Week 3 and Week 8
To measure the proportion of cohort with tacrolimus concentration within 80-125% of concentration target on post-transplant dosing day 4 (DD4), week 3 and week 8 - within 80-125% of Cssavg target (where Cssavg is the average steady state concentration).
Time taken to reach target tacrolimus concentrations post-transplant.
Median time to acceptable range (80-125% Cssavg) in the immediate post-transplant period.
Time with tacrolimus concentrations within the acceptable range over the first 8 weeks post-transplantation.
Time within acceptable range (80-125% of Cssavg) over the first 8 weeks post-transplant
Proportion of participants with acceptable trough tacrolimus concentrations immediately post-transplant (day 4).
Proportion of tacrolimus concentrations within 80-125% of Csstrough target (steady-state trough concentrations) on DD4
Number of tacrolimus dose adjustments made over the first 8 weeks post transplant.
Number of dose adjustments of tacrolimus based on therapeutic window approach (TWA) and/or Bayesian.
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