Solid Organ Transplant
Conditions
Keywords
Tacrolimus, Pharmacogenomics, Bayesian, Paediatrics
Brief summary
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.
Detailed description
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.
Interventions
DIAGNOSTIC_TESTGenotyping for CYP3A4 and CYP3A5 genes
Genotyping: 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)
DEVICEUse of NextDose platform
NextDose 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.
DRUGTacrolimus
Tacrolimus is administered to all patients post SOT at The Royal Children's Hospital (RCH)
Sponsors
Murdoch Childrens Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Intervention model description
This is an open-label trial with a prospective intervention arm and a retrospective standard of care comparator arm. Forty-five SOT recipients will be recruited from The Royal Children's Hospital Melbourne (with retrospective controls taken from the immediately prior 5 years). For all eligible SOT patients, a pre-emptive CYP3A5 and CYP3A4 genotype will be combined with a population PK model to predict optimal initial tacrolimus dose. In addition, genotype-informed Bayesian revised dosing will be applied to all transplant recipients over the subsequent 8-weeks post-transplant. The prospective arm will be compared with a retrospective arm (using standard mg/kg dosing plus therapeutic drug monitoring) where the primary outcome is the proportion of participants in each cohort with tacrolimus concentration (steady-state average concentration) within 80-125% of concentration target (Cssavg) on post-transplant dosing DD4, Week 3 & Week 8.
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
Participants will be assigned to the prospective arm if treated at Royal Children's Hospital who are receiving a solid organ transplant (SOT) (excluding repeat graft in liver transplant recipients, or lung or intestinal transplant) and who will be on tacrolimus as one of the main immunosuppressants post-transplant. Inclusion Criteria: * Age 1-18 years of age * Kidney, liver or heart transplant recipients * Participant and/or parent consent to the study (prospective arm only)
Exclusion criteria
* 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 * Known hypersensitivity to tacrolimus and/or its formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Post transplantation at Day 4, 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time taken to reach target tacrolimus concentrations post-transplant. | Post transplantation through first 8-week period | 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. | Post transplantation through first 8-week period | 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). | Post transplantation at 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. | Post transplantation at Week 8 | Number of dose adjustments of tacrolimus based on therapeutic window approach (TWA) and/or Bayesian. |
| Safety of genotype-informed Bayesian dosing within the first 8 weeks post transplant | From first dose of Tacrolimus through to 8 weeks post transplantation | Safety of genotype-informed Bayesian dosing, including description of number of clinical outcomes: rejection, donor-specific antibody formation; tacrolimus toxicities of new onset diabetes after transplantation. |
| Feasibility of genotype-informed Bayesian dosing and barriers to implementation. | From first dose of Tacrolimus through to 8 weeks post transplantation | To record any barriers or challenges that occur in using genotyping and Bayesian dosing for dose prediction of tacrolimus. These can include any technical failures of the NextDose platform for dosing predictions or data access. |
Countries
Australia
Contacts
CONTACTRachel Conyers
PRINCIPAL_INVESTIGATORRachel Conyers
Murdoch Childrens Research Institute
PRINCIPAL_INVESTIGATORDavid Metz, MBBS, PhD
Murdoch Childrens Research Institute
Outcome results
None listed