A living document now provides clinicians with advice on when to order pharmacogenomic testing before patient exposure to medications including carbamazepine, oxcarbazepine and phenytoin which are amongst those with the potential for severe adverse events.
The recommendations [link here] follow a Royal College of Pathologists of Australasia (RCPA) pharmacogenomics (PGx) project addressing a critical lack of standardised guidelines.
The RCPA said an estimated 250,000 hospital admissions annually are a direct result of medication-related problems which cost the health care system $1.4 billion per year. Yet two-thirds of these events were potentially preventable.
Associate Professor Luke Hesson, co-chair of the RCPA’s PGx Advisory Group, said pharmacogenomics was a growing field and that many common medications with the potential for harm have relevant prescribing guidance.
“PGx testing in Australia is reasonably well developed in terms of the range of medications and genes tested. However, there needs to be Medicare rebates for PGx tests in Australia, especially given that some of these tests are important for identifying patients at serious risk of toxicity,” he said in a statement from the RCPA.”
The guidance was that HLA-B*15:02 and HLA-A*31:01 alleles are associated with severe cutaneous and systemic adverse reactions to carbamazepine and oxcarbazepine, such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
It said the reactions can be fatal and typically occur within a couple of months of initial exposure to the anti-seizure medications.
Despite the potential for these severe reactions and testing for HLA-B*15:02 or HLA-A*31:01 being available in Australia, it is not currently rebated by Medicare.
Similarly genetic tests are recommended before initial prescribing of phenytoin or if a hypersensitivity reaction or therapeutic failure are suspected in patients already taking the drug.
The guidance said HLA-B*15:02 alleles are associated with severe cutaneous and systemic adverse reactions to phenytoin, such as DRESS, SJS and TEN.
As well, several CYP2C9 alleles are associated with variability in phenytoin metabolism, leading to an increased likelihood of therapeutic failure or adverse reactions.
The RCPA said as part of the pharmacogenomics project, it has submitted an application to the Medical Services Advisory Committee (MSAC) requesting public funding for human leukocyte antigen (HLA) testing for sensitivity to carbamazepine in patients with epilepsy.
The application is in the assessment process with a decision expected in 2025.
Increasing awareness
Associate Professor Hesson told the limbic that awareness of and support for pharmacogenomic testing varied across medical disciplines.
“I think the first thing is the genotype of particular genes involved in the metabolism of medications is just one factor as to whether a patient might respond…and the cocktail of medications that patients are on can impact the metabolism of one or the other.”
As well, “Environmental factors, for example, whether you smoke, whether you drink a lot, that can influence your expression and the activity of the enzymes that metabolise these drugs.”
He said the other issue facing clinicians was whether or not there was an alternative medication to offer patients.
Nevertheless, it was useful to have the information about whether patients had the necessary activity in particular pathways to effectively use or metabolise the proposed drug, he said.
“It certainly is the case that if you have a particular genotype, you will almost certainly get toxicity and so it’s good to know that so that you can lower the dose or you can use an alternative if available, or at least closely monitor them.”
Associate Professor Hesson, from Douglass Hanly Moir Pathology and UNSW Sydney, said requests for preemptive pharmacogenomic testing were increasing despite the lack of MBS funding.
“I think that we are winning the battle in terms of explaining the clinical utility of it – making people aware of the limitations but also of the utility.”
He noted that international bodies including in France and the UK have mandated DPYD testing.
“That’s not happening here yet but hopefully it will… and there have now been publications analysing how that has impacted the use of the drug or the incidences of toxicity.”
Meanwhile, an Australian study published recently [link here] has found the main barriers to implementation of pharmacogenomic testing by oncologists were the lack of financial reimbursements (82%) and perceived lengthy test turnaround time (76%).
The project was funded by Australian Genomics and conducted in partnership with the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) and the Pharmaceutical Society of Australia (PSA).