Using pharmacogenomics to personalise drug therapy: which drugs, when and how

SUMMARY

Pharmacogenomic testing provides information on whether a patient possesses gene variants that can influence drug exposure or response. It can be used as part of clinical decision-making to personalise drug therapy.

Pharmacogenomic testing can help identify patients at higher risk of serious adverse drug reactions or therapeutic failure, and sometimes it can explain unexpected adverse effects or poor efficacy in patients already on drug therapy.

As drug responses are influenced by many factors, pharmacogenomic test results must always be interpreted in the clinical context of the patient.

At the time of writing, tests for thiopurine methyltransferase (TPMT) (azathioprine, mercaptopurine, thioguanine), human leucocyte antigen B*57:01 (abacavir), and dihydropyrimidine dehydrogenase (DPYD) (5-fluorouracil, capecitabine) are Medicare-rebated. Pharmacogenomic testing is also recommended for several other drugs, such as allopurinol and clopidogrel, but these do not currently attract a Medicare rebate.

 

Introduction

Pharmacogenomics is the study of how a person’s genetic makeup affects their responses to drugs. Pharmacogenomic testing provides information on gene variants (genotype) that produce proteins involved in drug metabolism and transport, influencing the amount of drug patients are exposed to (pharmacokinetics), and proteins more directly involved in drug response, such as receptors and immune system mediators (pharmacodynamics).

In clinical practice, pharmacogenomic testing can sometimes help prescribing by serving as a tool to inform clinical decision-making.¹ It can identify patients at higher risk of serious adverse drug reactions or treatment failure, guiding selection of safer alternatives and avoiding trial and error.¹ It can also sometimes help explain poor drug efficacy or unexpected adverse effects. Pharmacogenomic-guided prescribing may reduce adverse drug reactions by up to 30% across a broad range of drugs,² help avoid severe hypersensitivity reactions,³ and be cost effective when weighing up the efficacy and safety balance for certain drugs.^4-10

 

Pharmacogenomic testing in clinical practice

Drug responses are influenced by many factors, such as disease severity, age, concomitant drugs, organ function, and adherence, so pharmacogenomic results must always be interpreted in the overall clinical context.

Pharmacogenomic tests can be ordered for specific individual genes of interest, for example human leucocyte antigen (HLA); this is known as targeted testing. Another approach is panel testing, which involves testing multiple genes (typically 9 to 12) at the same time. These panels include genes for major drug-metabolising cytochrome P450 (CYP) enzymes, such as CYP2C19 and CYP2D6.²

Some gene variants are more common in certain populations, for example, the HLA-B*58:01 allele in the Han Chinese population.¹¹ Therefore, some guidelines suggest that pharmacogenomic testing for gene variants that are more common in specific populations should be limited to people from these populations. However, determining the indication for pharmacogenomic testing based solely on the presumed geographic ancestry of a person is not advised, particularly given the admixture of the Australian population. Rather, the indication for testing should be determined based on the clinical context.

Pre-emptive pharmacogenomic testing

Pre-emptive pharmacogenomic testing is conducted prior to prescribing and the results can help with drug and dose selection. As well as reducing risk of adverse events, pre-emptive testing can streamline the prescribing of drugs with strong pharmacogenomic evidence by reducing the need to wait for test results at the point of prescribing. For example, testing of HLA-B*58:01 is recommended prior to prescribing allopurinol. Carriers of this allele should not be prescribed allopurinol due to the increased risk of hypersensitivity; in these people, other urate-lowering drugs are preferred.¹¹

Concurrent pharmacogenomic testing

Concurrent pharmacogenomic testing is done in acute clinical scenarios at the time of prescribing, before evaluation of drug response is possible. A good example is when clopidogrel is prescribed following coronary stent insertion to prevent thrombosis, and a CYP2C19 test is requested concurrently to determine if it is the most suitable antiplatelet drug. The CYP2C19 genotype impacts the metabolism and activation of clopidogrel. Individuals with a CYP2C19 variant associated with poor clopidogrel metabolism have an increased risk of stent thrombosis due to reduced clopidogrel activation. In these patients, an alternative antiplatelet drug that does not rely on CYP2C19 for activation, such as ticagrelor, can be considered.¹²

Reactive pharmacogenomic testing

Reactive pharmacogenomic testing is conducted after an unexpected drug-related problem occurs at standard doses, such as intolerable adverse effects or unexplained poor efficacy. The information can help diagnose the problem and guide adjustment of therapy (e.g. adjustment of dose, selection of an alternative drug).¹³ For example, the CYP2C9 gene is associated with warfarin metabolism and the VKORCI gene is linked to warfarin sensitivity. A person who carries CYP2C9 and VKORCI gene variants may have reduced warfarin metabolism and increased warfarin sensitivity and is therefore at risk of over-anticoagulation and bleeding. Switching to an alternative oral anticoagulant, such as a direct-acting oral anticoagulant, could be considered.¹⁴

Incidental pharmacogenomic testing

Patients may bring a pharmacogenomic test report to a medical appointment. Some patients may have unrealistic expectations about the benefits of pharmacogenomic testing, and make suggestions about their medications after reading reports, not necessarily understanding that multiple factors are considered when prescribing.¹⁵ It is rarely necessary to change effective drug treatment based on pharmacogenomic reports only.

 

Indications for pharmacogenomic testing

The Royal College of Pathologists of Australasia (RCPA) recently developed a list of pharmacogenomic indications in Australia.¹⁶ Drugs were sorted into one of 3 categories based on expert working group consensus: ‘recommended’, ‘consider’ and ‘no consensus’. When initiating a drug in the ‘recommended’ list (Table 1), the RCPA expert group recommends that pharmacogenomic testing should be done to inform prescribing, as these drugs have the greatest clinical benefits if testing is implemented. For drugs in the ‘consider’ and ‘no consensus’ categories, the decision to test, and timing of testing, may depend on the clinical question and experience of the clinician with pharmacogenomics. For specific guidance on prescribing drugs in individuals who carry certain gene variants, including those listed in Table 1, clinicians can refer to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The CPIC is an international organisation that creates evidence-based guidelines on how to use genetic information to guide drug therapy.

Table 1 Drugs for which pharmacogenomic testing is recommended by the Royal College of Pathologists of Australasia [NB1][NB2]¹⁶

Drug name	Gene variant of interest	When to test
Reason for testing: to avoid drug hypersensitivity reactions (prescribe an alternative drug if test is positive)
Abacavir	HLA-B*57:01	before initial prescribing OR when a hypersensitivity reaction to one of these drugs is suspected
Allopurinol	HLA-B*58:01
Carbamazepine Oxcarbazepine	HLA-B*15:02 and HLA-A*31:01
Phenytoin	HLA-B*15:02 and CYP2C9	before initial prescribing OR when a hypersensitivity reaction is suspected (HLA-B*15:02) [CYP2C9 testing can be considered when therapeutic failure or other adverse effects are suspected]
Reason for testing: to avoid severe adverse drug reactions (reduce the dose or prescribe an alternative drug if test is positive)
Capecitabine 5-fluorouracil	DPYD	before initial prescribing OR when a severe adverse effect is suspected
Azathioprine Mercaptopurine Thioguanine	TPMT and NUDT15
Reason for testing: to avoid therapeutic failure (increase the dose or prescribe an alternative drug if test is positive)
Clopidogrel	CYP2C19	before or at the time of initial prescribing OR when therapeutic failure or adverse effects are suspected
Voriconazole	CYP2C19	before initial prescribing in patients with invasive mycosis OR when therapeutic failure (e.g. unexpectedly low serum concentration of voriconazole) or adverse effects are suspected
CYP = cytochrome P450 enzyme; DPYD = dihydropyrimidine dehydrogenase; HLA = human leucocyte antigen; NUDT15 = nudix hydrolase 15; TPMT = thiopurine methyltransferase NB1: At the time of writing, tests for TPMT (azathioprine, mercaptopurine, thioguanine), HLA‑B*57:01 (abacavir) and DPYD (5-fluorouracil, capecitabine) are rebated by Medicare. NB2: For specific guidance on how to use pharmacogenomic test results when prescribing specific drugs (e.g. determining doses, quantifying risk of an adverse event), refer to guidelines from the Clinical Pharmacogenetics Implementation Consortium.

 

Ordering pharmacogenomic tests

Pharmacogenomic testing is available through several providers in Australia using either paper-based referrals or online portals. Referrals should state the reason(s) for testing and any pertinent clinical details, such as drug history and history of response. When selecting a provider, ensure the laboratory is certified by the National Association of Testing Authorities and accredited by the RCPA. All providers give test reports with prescribing guidance from the CPIC. Some providers offer consultation services with clinical pharmacologists or pharmacists.

Pharmacogenomic testing uses blood or buccal (cheek swab) samples. Both methods are effective for obtaining the genetic material required. The average turnaround time for pharmacogenomic tests in Australia is typically 5 to 10 business days after a laboratory receives the sample. DNA is stable, so samples can generally be transported over long distances without the need for freezing.

The cost of pharmacogenomic testing in Australia can vary depending on the provider and the specific tests being conducted. In general, a panel (multiple genes) test costs about $150 to $200 and targeted tests are between $50 and $200; tests are typically funded by the patient.¹⁷ At the time of writing, testing for thiopurine methyltransferase (TPMT) (azathioprine, mercaptopurine, thioguanine), HLA-B*57:01 (abacavir) and dihydropyrimidine dehydrogenase (DPYD) (5-fluorouracil, capecitabine) attract a rebate by Medicare; all other tests are currently not rebated. Broader application of pharmacogenomic testing is anticipated with widespread reimbursement of tests. Currently, panel testing is more cost-effective than targeted testing and is the approach most used in clinical practice.

 

Challenges and pitfalls of pharmacogenomic testing

Pharmacogenomic test results do not always provide an answer to a clinical problem. Many clinical (e.g. age, comorbidities), non-clinical (e.g. adherence, health literacy), socioeconomic and unknown factors influence drug responses, and the overall clinical context of the patient must always be considered. Monitoring of responses to therapy is important for all drugs, independent of the original prescriber.

Pharmacogenomic testing may be less informative if the patient has already started treatment (reactive testing) and an established clinical assessment or marker is available to guide prescribing decisions.

Prescriber knowledge and confidence in using pharmacogenomics are low in Australia.¹⁸ Pharmacogenomics can be difficult to apply clinically, particularly in patients with multimorbidity and polypharmacy where phenoconversion (when the phenotype differs to that expected from the genotype alone) can occur. For example, based on a pharmacogenomic test, a person could be a CYP2D6 rapid metaboliser. However, the person might experience drug effects similar to those of a ‘slow metaboliser’ if they are taking a medication that inhibits the activity of the CYP2D6 enzyme, or due to liver dysfunction that reduces enzyme activity. Misinterpretation of results and rote application of generic prescribing advice can lead to inappropriate prescribing. Professional advice should be sought from experienced colleagues, pharmacists accredited in pharmacogenomics, and clinical pharmacologists (often available from test providers) when starting to use pharmacogenomic-guided prescribing.

Adequate training of prescribers is required to ensure they can counsel patients and improve their knowledge and understanding of the benefits and limitations of pharmacogenomic testing.

Access to pharmacogenomic testing may be limited by socioeconomic factors, potentially exacerbating existing health disparities.

Genetic information is highly sensitive and personal. Unauthorised access could lead to discrimination (e.g. employment, insurance).

Ideally, given the applicability of pharmacogenomic test results over a lifetime, they should be available to prescribers across healthcare settings, which requires storing results in interoperable systems (e.g. My Health Record).

Pharmacogenomic tests in Australia identify genetic variants common in Europeans, with reduced coverage of other geographic ancestries, including those from the Middle East, and Aboriginal and Torres Strait Islander people. Therefore, the decision to do pharmacogenomic testing should not be based on geographic ancestry alone.

Patients may have unknown genetic variants that influence drug responses in unexpected ways. Patients may also carry genetic variants not currently included in testing procedures, which could potentially lead to misclassification of patients. Standardisation of the genetic variants examined across pharmacogenomic testing laboratories is required.

Contraindications or warnings based on pharmacogenomic testing are included in the approved product information for several drugs on the RCPA’s ‘recommended’ list (e.g. capecitabine). The medicolegal consequences of misinterpreting test results, or not using pharmacogenomics for these drugs in patients who experience severe adverse drug reactions, are currently unknown.

 

Conclusion

Pharmacogenomics can be used to help personalise drug therapy for patients. When indicated, pharmacogenomic testing can help identify patients at higher risk of serious adverse drug reactions or therapeutic failure, and sometimes it can explain unexpected adverse effects or poor efficacy. Australian and international guidance is available on which drugs may benefit most from pharmacogenomic-guided prescribing, when to order testing, and how to interpret pharmacogenomic test results. Several commercial providers in Australia offer single gene and panel testing. Pharmacogenomic test results should always be considered within the clinical context of the patient.

This article was finalised on 8 May 2025.

Conflicts of interest: Sophie Stocker is the lead investigator of a Gilead-funded trial investigating the use of pharmacogenomics to deliver individualised therapy of antifungal drugs. She is also leading a trial evaluating implementation of pharmacogenomics in aged care. Sophie received complimentary registration to the 2024 Pharmaceutical Society of Australia conference as an invited speaker on pharmacogenomics. Sophie is the co-chair of the Royal College of Pathologists of Australasia (RCPA) Pharmacogenomics Working Group, which developed the RCPA’s list of indications for pharmacogenomic testing in Australia.

Thomas Polasek receives consultancy fees from Sonic Genetics for providing advice on interpretation of pharmacogenomic test results. Thomas is a member of the RCPA pharmacogenomics working group.

This article is peer reviewed.

 

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