Patients sometimes don’t respond as expected to common medications, and genetic variants might be responsible more often than you’d think. Pharmacogenomic testing can help GPs understand and manage issues like treatment failure and adverse effects, with some important limitations, experts say.
Here’s how it works—and when it’s most likely to be useful in general practice.
Genetic variants are thought to explain about 30 to 40% of medication response, says Dr Rebecca Purvis, a senior genetic counsellor with Bupa and genomics lecturer at the University of Melbourne.
“And nearly all individuals, regardless of background, will have at least one gene variant that affects their response to commonly prescribed medications.”
The cytochrome P450 (CYP450) enzyme family is of particular interest, and hundreds of functional genetic variants (called polymorphisms) in these genes can influence how medications are metabolised, she explains.
Some patients are poor metabolisers, so active drugs may accumulate to higher-than-expected levels, increasing the risk of adverse effects. With prodrugs, poor metabolisers may experience reduced efficacy because insufficient active drug is produced.
In contrast, rapid or ultra-rapid metabolisers may fail to achieve therapeutic drug concentrations with active medications, or experience rapid conversion of prodrugs into active metabolites, increasing the likelihood of dose spiking and adverse reactions.
Pharmacogenomic testing enables doctors to learn more about their patients’ drug metabolism, which can affect how safe and efficacious certain drugs will be for that person.
It facilitates a more tailored approach to prescribing, Dr Purvis says, noting that the reports include recommendations to optimise medication choice and dosage for the particular patient.
“If we can access genetic information early and use it when first prescribing, we have a higher likelihood of getting a better medication to that individual faster.”
Clinical Scientist Professor Luke Hesson, Department Manager of Genetics at Douglass Hanly Moir Pathology, is the co-chair of the Royal College of Pathologists of Australasia’s Pharmacogenomic Advisory Group—which developed guidance on indications for pharmacogenetic testing in Australia.
Not every patient needs testing, he stresses. “But in certain scenarios, and when specific medications are being considered, then it’s definitely relevant.”
Muscle toxicity with statin therapy is a key example, he says.
Variants in a transporter gene known as SLCO1B1 can impair hepatic uptake of some statins, he explains. This causes plasma concentrations of that statin to rise, leading to accumulation in other tissues—firstly muscles.
“It can happen in as many as 20% of patients. And noncompliance is a big issue because of that.”
“So if you identify those patients who are susceptible to it, they can be given an alternative which doesn’t cause this muscle toxicity.”
Common culprits include simvastatin, atorvastatin and lovastatin.
Test reports typically include guidance about alternatives, he adds.
Genetic variants can sometimes be responsible for unexpected responses to opioid analgesics, Professor Hesson says.
Codeine, which must be converted into morphine via the CYP2D6 enzyme, is a prime example.
“If the enzyme that controls that process is lower in activity because of the patient’s genotype, then they less readily activate codeine into morphine.” Patients identified as CYP2D6 poor metabolisers will not receive adequate pain relief and can be prescribed alternative opioids.
Medications like fluoxetine, fluvoxamine and sertraline are frequently prescribed in primary care, yet treatment response can be highly variable.
“There are patients who have genotypes which means they’re more likely to have adverse reactions to these medications, or that they’re ineffective or don’t work as well,” Professor Hesson says.
“It can take many weeks to months for an antidepressant to start to be effective. If it’s the wrong choice or dose, then it’s many more months to refine that.”
“Pharmacogenetic tests can reduce that trial and error and bring relief to a patient much sooner.”
Dr Purvis agrees depression is a key use case, citing a study that found patients who were prescribed antidepressants with pharmacogenomic guidance were 70% more likely to achieve remission.
Professor Hesson notes testing may also be appropriate for common medications like proton pump inhibitors and antiemetics, as well as some oncology, cardiovascular, rheumatology and infectious disease therapies.
Pharmacogenomic reports often include guidance for dozens of medications spanning multiple specialties, he adds.
There are three approaches to pharmacogenomic testing, Professor Hesson explains.
Proactive testing before initiating a medication in increasingly common as GPs see the value in getting ahead of potential issues, he says.
“And when we provide a report, it will contain a specific comment about the medications that they’ve indicated on the request form.”
Reactive testing is used to investigate unexpected adverse reactions or lack of therapeutic response—and currently has the most utility, he says.
Pre-emptive testing, or testing before you even contemplate prescribing, can be helpful for patients who’ve been prescribed many medications in the past, or if you’re likely to prescribe something in future.
It can be harder for patients to see the benefits of pre-emptive testing, he says, although one study found it reduced adverse drug reactions by 30% compared with a control group.
“Pharmacogenetic testing is not a panacea that will explain a lack of response or an adverse reaction to all medications,” Professor Hesson emphasises.
Many common drugs have no established pharmacogenomic associations, and even when genetic variation is relevant, it may only partially explain the clinical picture.
Nor do tests cover every possible variant, he says, noting a normal result does not exclude the possibility of an undetected genetic contributor.
“And as with all genetic testing, they tend to be highly weighted towards European variants, because the overwhelming amount of data in the literature is from European populations.”
“Certain ancestry backgrounds, say East Asians or First Nations peoples, may have variants that are not being tested.”
Testing is still helpful in these populations, he stresses.
“If there is a variant that is functionally relevant, that is useful information regardless of the ancestry of the patient.”
The out-of-pocket cost, which is typically about $200, can also be a limiting factor. Some health funds offer rebates or discounted home testing kits for members.
Medicare rebates are not currently available for panel pharmacogenomic testing, but Dr Hesson notes there are four MBS items for genetic testing to help mitigate risk of hypersensitivity or severe dose-related toxicity when prescribing azathioprine, abacavir, fluoropyrimidines, and carbamazepine/oxcarbazepine.
If you order a test, Professor Hesson recommends noting any specific medications to investigate and why. It’s also important to list all the patients’ medications, as polypharmacy can complicate interpretation. In these cases, a clinical pharmacologist is often consulted.
Reports can be 15 or 20 pages long and may seem daunting, but they’re best viewed as decision-support tools, Professor Hesson says.
“They’re not prescriptive, they’re not directive. The GP will have a much better understanding of the history of the patient and what other medications and conditions would be relevant.”
Dr Purvis says some reports use a traffic light system, with red indicating significant risk that warrants consideration of an alternate drug or dose. Orange is “a little bit more nuanced,” suggesting an altered response is possible, while green indicates the person is a typical metaboliser, she explains.
Pharmacists can provide helpful advice about reports, and a home medication review (HMR) includes pharmacogenomic considerations, she adds.
“Studies that have looked at this combination between pharmacogenomics and HMR overseas have seen significantly improved patient outcomes.”
RCPA | Pharmacogenomic Indications in Australia
RACGP | Genomics in General Practice
NSW Health | Centre for Genetics Education
PRECISE | Genomics in Primary Care
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