A living document now provides clinicians with advice on when to order pharmacogenomic testing before patient exposure to medications including mercaptopurine, thioguanine and clopidogrel, 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 said several TPMT and NUDT15 alleles were associated with variability in mercaptopurine and thioguanine metabolism, leading to an increased likelihood of severe adverse reactions such as myelotoxicity or hepatotoxicity.
It also noted that the pharmacokinetics of mercaptopurine and thioguanine may be modified by non-genetic factors such as age, co-morbidities and exposure to other drugs taken concurrently.
“Testing for TPMT alleles is currently rebated by Medicare; a laboratory may include NUDT15 for no additional charge,” it said.
The guidance on clopidogrel was that several CYP2C19 alleles were associated with variability in the anti-platelet medication’s metabolism. Affected patients were therefore at an increased likelihood of therapeutic failure or adverse reactions.
While testing for CYP2C19 alleles is available through several clinical laboratories in Australia, it is not currently rebated by Medicare.
The PGx project also suggested pharmacogenomic testing for several VKORC1, CYP2C9 and CYP4F2 alleles should be considered ahead of prescribing warfarin.
Again, testing for these alleles was available through several clinical laboratories in Australia but not currently rebated by Medicare.
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.”
Funding issue
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 was the lack of financial reimbursements (82%) and perceived lengthy test turnaround time (76%).
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 DPYD genotyping to predict fluoropyrimidine-induced toxicity.
The application is in the assessment process with a decision expected in 2025.
The pharmacogenomics 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).