Pharmacogenomics: what pharmacists should know

Case Scenario

Kiet, a 45-year-old man of Thai ethnicity, presents to your pharmacy with a prescription for allopurinol. He has been prescribed this to treat his frequent gout flares, for which he usually takes ibuprofen. Kiet is worried, as he recalls his brother having a ‘bad reaction’ to a gout medicine in the past, and because he has never had to take any regular medicines before. You look in the Australian Medicines Handbook and note that Kiet’s ethnicity may increase his risk of having the HLA-B*58:01 allele, which significantly increases the risk of hypersensitivity reactions with allopurinol. You ask Kiet, but he does not recall having had any genetic tests in relation to this.

Introduction

Medication-related problems have a significant impact on individuals and Australia’s healthcare system, costing $1.4 billion annually and causing 250,000 annual hospital admissions.¹ Half of medication-related harm is believed to be preventable.¹ Consequently, medicines safety is Australia’s 10th National Health Priority Area, and the work of pharmacists is integral to its achievement.²

Pharmacogenomic testing is a tool that can be used to personalise medicine management. It has been shown to reduce adverse events, healthcare utilisation and healthcare costs.^3-6

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What is pharmacogenomic testing?

Pharmacogenomics is a field of precision medicine using genetic testing (genotyping) to predict an individual’s response to a medicine. This assists guided prescribing, with potential to reduce the risk of an adverse effect or improve efficacy.⁷ Its use is now possible through commercial providers who collect samples through ‘do it yourself’ cheek swabs, or via pathology laboratories. Additionally, it is becoming more affordable, with panel tests costing less than $200.^8,9 However, pharmacogenomic testing remains an underutilised tool in Australia due to low practitioner and public knowledge, low confidence to use the technology and little public subsidy.¹⁰

Genetic testing seeks to identify changes in DNA – the code made up of adenine, cytosine, guanine and thymine that tells your cells how to make proteins.⁷ Genetic variation inherited from each parent (alleles) results in proteins such as drug-metabolising enzymes being made differently, which can change protein function. The functional changes can be significant, amounting to >100-fold differences in the risk of developing severe hypersensitivity reactions, up to 27-fold differences in enzymatic activity, or up to 15-fold differences in drug exposure in extreme cases.^11,12

How is pharmacogenomic testing used?

Pharmacogenomic test results can help predict how an individual will respond to a medicine. Ideally and most commonly, testing is performed prior to initial prescribing of a medicine (proactively) so it may inform dosing and/or the need for alternative therapies. 

The drug-gene associations of interest (for guiding medicine selection and dosing) are those associated with ^6,10,13-15:

1. Hypersensitivity reactions to medicines, e.g. genetic variants in the human leucocyte antigen (HLA) can significantly increase the risk of severe and life-threatening hypersensitivity reactions to commonly used medicines, including abacavir, carbamazepine, allopurinol and phenytoin.
2. Drug metabolism and transportation, e.g. genetic variants in drug metabolism enzymes include thiopurine methyltransferase (TPMT) which affects the metabolism of thiopurines (e.g. azathioprine) and the risk of adverse events.
3. Drug targets, e.g. genetic variation in VKORC1 (target for warfarin) and OPRM1 (target for codeine and morphine) are associated with altered treatment responses.

Interpretation of pharmacogenomic tests for drug-metabolising enzymes (e.g. CYP450 enzymes) typically categorises individuals into metaboliser states such as poor, normal, rapid of ultrarapid.¹² CYP metaboliser status can inform decisions around dose and/or alternative therapies with the aim of reducing adverse effects or improving efficacy, depending on the drug (or pro-drug). For example, an individual who is a CYP2C19 rapid metaboliser is expected to metabolise citalopram and escitalopram more quickly, increasing the likelihood of therapeutic failure by reducing the plasma concentration.¹⁶ Consequently, an alternative antidepressant not predominantly metabolised by CYP2C19 (e.g. paroxetine) may be preferred.¹⁶ Table 1 shows further examples of drug-gene pairs that have potential actionable outcomes.

Proactive versus reactive testing

An example of proactive testing, before treatment is initiated, is a test for HLA-B*58:01 carrier status.²⁰ If positive, the test indicates an individual has a significantly increased risk of a severe or life-threatening hypersensitivity reaction to allopurinol. In this case, the prescriber would know to select an alternative urate-lowering agent such as febuxostat.²⁰ Conversely, if they have HLA-B*58:01 negative or non-carrier status, an individual does not have a higher risk of hypersensitivity and allopurinol can be prescribed as normal, following appropriate guidelines.²⁰

A similar test could be used to assess a patient’s CYP metaboliser status prior to initiating a medicine to guide treatment and dosage decisions, e.g. CYP2C19 and clopidogrel (see Table 1). A proactive pharmacogenomic test for CYP enzyme alleles, however, typically has less binary findings when compared with HLA tests.

In contrast to proactive testing, results can be used in the diagnosis and/or understanding of therapeutic failure or an adverse effect (i.e. reactive testing).¹⁸ For example, in a person recently initiated on citalopram describing a poor response, a pharmacogenomic test to assess CYP2C19 metaboliser status could potentially explain subtherapeutic plasma concentration.¹⁶

A further example of reactive testing is reflected in a recent Australian case study concerning a 72-year-old man of Vietnamese ancestry who developed a pruritic erythematous rash 10 days after initiating allopurinol, for which he sought medical attention but was advised to continue with allopurinol treatment.²¹ Over 2 weeks later he was admitted to hospital with drug reaction with eosinophilia and systemic symptoms (DRESS). Genotyping revealed HLA-B*58:01 carrier status. As testing was not conducted earlier (either proactively prior to treatment or reactively at the initial presentation of symptoms), allopurinol was not discontinued earlier, leading to further complications, including acute kidney injury and liver injury.²¹

Limitations

Practitioners should be aware that pharmacogenomic tests, like kidney and liver function tests, have potential limitations, as the association between gene and medicine response is not perfect.

These limitations include, for example, that it is still possible for a HLA-B*58:01 non-carrier to experience a hypersensitivity reaction to allopurinol.²⁰ Additionally, the evidence base for pharmacogenomics is dominated by studies conducted in populations with European ancestry and, as such, associations with drug response in other ancestries is less certain. In Australia, pharmacogenomics in Aboriginal and Torres Strait Islander populations is poorly studied.²² Achieving equity in pharmacogenomics will require further research investment.²²

Of important consideration is that response to a medicine is also determined by many non-genetic factors such as comorbid conditions, polypharmacy, adherence, diet, weight and smoking status. Consideration of all relevant factors is essential.

Ethical, legal and social factors

With pharmacogenomics, concerns of revealing sensitive information appears less of an issue than with genetic tests identifying disease risk or genealogy tests.²³ Unlike other genetic tests, pharmacogenomic test results provide clear links to interventions – that is, a change of medicine or dose – and have little value for individuals or family members who are not prescribed the medicine. An exception to this may be family members of HLA carriers who are more likely to also be carriers.²⁴ Nevertheless, the Human Genetics Society of Australasia’s recent position statement calls for governments to have a more active role regarding legislation concerning new genetic technologies, including pharmacogenomics. The statement includes insurance industry use of genetic information.²⁵ As with any testing or intervention, pharmacists will be aware of the requirement for informed consent.

Pharmacogenomic testing in Australia

Studies suggest up to 96% of Australians have at least one ‘actionable’ drug-gene variant.²⁶ (Note: actionable variants are only relevant to an individual when they become a candidate for a medicine affected by that specific genetic variant.) The Medicare Benefits Schedule (MBS) currently subsidises two single gene pharmacogenetic tests: thiopurine methyl transferase (TPMT) And HLA-B*57:01.¹⁰ They are indicated to screen for the genetic variants that increase the risk of severe adverse drug reactions (to thiopurines and abacavir, respectively), prior to prescribing.^27,28

Several commercial organisations offer testing in Australia. Samples from blood collected at a pathology laboratory or an at-home cheek swab can take up to 10 days to return results.^8,9 Many pharmacies currently stock self-collection kits, or can order these. 

Barriers to use

Several barriers have prevented widespread uptake of pharmacogenomic testing. At the practitioner level, these barriers include poor knowledge and practitioner confidence, lack of education opportunities, little public funding for testing, uncertain models of practice, roles and workflows, and lack of integrated clinical decision support for pharmacogenomics in prescribing and dispensing software.^29,30

Guidance for prescribers, pharmacists and consumers on who to test is also lacking. The main guidance available is for applying pharmacogenomic test results, leaving who to test up to each practitioner and their respective health system context. A project funded by an Australian Genomics grant is currently producing Australian indications for pharmacogenomic testing, however.

Pharmacists would be aware, that pharmacogenomics is frequently mentioned in Therapeutic Goods Administration (TGA) approved product information (PI), the Australian Medicines Handbook (AMH) and the Therapeutic Guidelines (eTG), however guidance is frequently conflicting or variable in the depth of information provided. For example, the codeine PI states, ‘contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers’ and the AMH entry states ‘testing is not readily available’; however, neither describes how to identify these patients.^31,32

Clearly there is much work to be done to address potential barriers, and to incorporate pharmacogenomics into healthcare, given the potential for improving drug safety and efficacy.

Appropriate resources

Prescribing guidelines for practitioners developed from evidence reviews are provided by the Dutch Pharmacogenetics Working Group (DPWG), the Clinical Pharmacogenetics Implementation Consortium (CPIC) and others.^33,34 CPIC has published 26 evidence-based gene/drug clinical practice guidelines covering more than 100 commonly used drugs.^18,33

Another good source of information for pharmacists is PharmGKB.org, which collates the information from essential pharmacogenomic guidelines (e.g. CPIC, DPWG) and available pharmacogenomic prescribing information from drug regulators (e.g. United States Food and Drug Administration and the European Medicines Agency). PharmGKB has 289 clinical annotations with the highest (Level 1A) evidence, denoting an actionable variant.^34,35

Knowledge to practice 

It has been proposed that pharmacists play a stewardship role, like current roles with antibiotics and opioids.³⁶ Presently in Australia, pharmacists are unable to independently order tests; however, international models of practice are often pharmacist-led, and Australia may follow these examples in the future.³⁷

Pharmacists are key to pharmacogenomic-guided prescribing and can potentially provide benefit in many areas. These include pre-test counselling and education, decisions around ordering, obtaining consent, interpretation of results, integration of results with current medicines, guidelines and non-genetic factors, counselling on results, and addition of results into practitioner software (where possible). Pharmacists have the core skills required for integration of pharmacogenomics into the broader clinical picture of each patient, including consideration of other factors such as age, gender, concomitant medicines, renal function, inflammation, smoking status, diet and weight. A key requirement for the success of a pharmacogenomic testing service is providing patients and practitioners with results that are meaningful. Pharmacogenomic test results are most useful when presented with recommendations as a summary report.

It is important that pharmacogenomic reports are equally accessible to all relevant health professionals to ensure collaboration, shared decision-making, and to facilitate successful and sustainable service provision. 

Conclusion

Pharmacogenomic testing and guided prescribing is a tool that pharmacists can promote in their practice to help improve medicine safety and efficacy.The first steps to its implementation in your practice are to gain knowledge and understand the process around ordering tests. Online guidance is freely available, along with support from numerous providers.

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Key points

• Pharmacogenomic testing can help inform prescribing, and evidence demonstrates it can reduce adverse drug effects and improve efficacy of treatments.
• Online resources are available in the form of International Consensus Guidelines at PharmGKB.org to guide ordering and interpretation.
• Pharmacists play a key role in the use of pharmacogenomics in clinical practice, including providing education to prescribers and consumers.

References

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36. Mostafa S, Polasek TM, Sheffield LJ, Huppert D, Kirkpatrick CMJ. Quantifying the Impact of Phenoconversion on Medications With Actionable Pharmacogenomic Guideline Recommendations in an Acute Aged Persons Mental Health Setting. Frontiers in Psychiatry. 2021;12.
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Our authors

Dr Sophie Stocker (she/her) BSc (Hon I), PhD is a Senior Lecturer at the School of Pharmacy, University of Sydney. She is a member of the RCPA Pharmacogenomics Working Group developing an indications policy for pharmacogenomic testing in Australia.

Dr Stephen Hughes (he/him) BPharm, MPhil, PhD is a lecturer at the School of Pharmacy, University of Sydney, and a community pharmacist. He has recently been involved in an NHMRC and Australian Genomics national consultation to develop research priorities for pharmacogenomics.

Our reviewer

MYFANWY Graham (she/her) BNat, MPharm

Conflict of interest declaration

Dr Sophie Stocker is on the scientific board of 23strands and consults to Nutromics and Bellberry. She is also the recipient of research funding from Gilead.