Background
Medicines safety is a priority issue for the Australian public and in particular for children with cancer given necessary use of high-risk and multiple medicines (polypharmacy) and the common occurrence of unplanned emergency presentations and hospital admissions consequent to adverse medicines events (AME) and symptom driven complaints (1). The number of cancer-related hospitalisations in Australia has steadily increased with an annual cost of 1.4 billion to the Australian healthcare system(1). Events are often linked to suboptimal medication selection, dose titration, and monitoring for expected toxicities and efficacies, consequent to a ‘one size fits all’ approach.
Objective
PRIORITY-P is an innovative precision therapy randomised control trial program that will discover, translate, implement and evaluate an evidence based approach to pharmacogenomic (PGx) medicine optimisation in paediatric oncology oncology cohorts. The primary end point is a reduction in AME in those patients with actionable pharmacogenomic variants.
Method
This first of its kind in paediatric oncology RCT will randomise patents to receive pharmacogenomics (PGx) guided prescribing (study arm) or standard of care (SoC) (control arm) for a period of 12 weeks. The patients will be followed up for a minimum of 12 months. Whole genome sequencing will be used to report on TPMT/NUD15 and a broader number of actionable variants in the study arm. Ped-PRO-CTCAE prospective reporting survey for parent/carer will be used to assess therapy symptoms, followed by formal CTCAE grading of symptoms by academic pharmacists. Health economics analysis will involve actual costs calculation collected via the Department of Health and the Centre for Victorian Data Linkage (CVDL) and Services Australia.
Results
We piloted using whole genome sequencing to call diplotypes for a range of pharmacogenes. This pipeline has been successfully piloted on the ACTive cohort (n=100). Two tools for genotyping were used to develop a consensus call (Aldy, Cyrius or Stargazer). A fit-for purpose clinical report has been developed incorporating international guidelines for metaboliser states and therapeutic implications.
Conclusion
We have piloted a WGS bioinformatic approach call pharmacogenes. This approach repurposes WGS for childhood cancer patients in a precision medicine approach to reduce AME.