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What is pharmacogenomics?
Genetic variations play a role in our ability to metabolise and respond to drugs, both in terms of efficacy and toxicity. Pharmacogenomic testing assesses the type of response a patient may have to a particular drug. Testing before prescribing medication can provide information about the likely effectiveness or risk of side effects for the patient.1,2
Pharmacogenetics versus pharmacogenomics
While pharmacogenetics examines the variability in response due to genetic variations in genes that metabolise drugs, pharmacogenomics is a broader term that refers to the involvement of all genes in determining drug response. The two terms are often used interchangeably.3–5
The ultimate goal of pharmacogenomics is the ability to target or ‘tailor’ drug therapy to individuals: being able to prescribe the right drug at an appropriate dose to maximise efficacy and avoid adverse effects. This goal feeds into the wider concept of personalised medicine, where an individual’s genetic profile is used to make decisions about all aspects of healthcare
(ie prevention, diagnosis, treatment).1,5
How genetic polymorphisms affect drug metabolism
Genetic variation can affect:5
- pharmacokinetics – how the drug metabolised by the body is affected by genetic variations in metabolising enzymes
- pharmacodynamics – what effect the drug has on the body is influenced by genetic variations in drug targets (eg receptors).
Pharmacogenomics testing analyses genes involved in these two pathways.
One example is the cytochrome P450 genes, which produce enzymes involved in drug metabolism. P450 enzymes account for 70–80% of enzymes involved in drug metabolism.5 Common variations in P450 genes can affect the function of the enzymes produced, which in turn affects the metabolism of some drugs. For example, drugs may be metabolised too quickly (ie higher dose needed for effect) or too slowly (ie lower dose needed for effect).
Genetic variations give rise to four different phenotypes in terms of drug response:1
- Poor metabolisers who have markedly reduced or absent enzyme activity.
- Intermediate metabolisers with reduced enzyme activity.
- Extensive (or normal) metabolisers.
- Ultrarapid metabolisers who have high enzyme activity.
Cytochrome P450 genes
Cytochorome P450 genes follow a certain naming system.6 For example, CYP2D6 is made up of the following codes:
- cytochrome P450 enzyme (CYP) – indicating it is part of the cytochrome gene family.
- 2 – a number associated with a specific group within the gene family.
- D – a letter which represents the gene subfamily.
- 6 – a number referring to the specific gene within the subfamily. This gene can then have different forms or alleles.
- CYP2D6*1 – allele 1 produces normal enzyme function
- CYP2D6*4 – allele 4 produces enzyme with no activity
- CYP2D6*10 – allele 10 produces enzyme with decreased activity.
Codeine is a common analgesic metabolised by CYP2D6 enzymes (Figure 1).7
Codeine → CYP2D6 → morphine
Benefits of pharmacogenomics
The benefits of pharmacogenomic testing arise from the ability to tailor medication to the individual: specifically, to predict the correct dose to avoid toxicity or adverse events, and to know whether a particular drug will be effective in any given patient.
The benefits of pharmacogenomics include:1,2
- achieving optimal drug doses quickly – the trial-and-error approach combined with repeated monitoring could be avoided
- minimising toxicity and adverse effects – knowledge of a patient’s genetic profile could reduce the likelihood of adverse outcomes and help direct clinicians towards suitable alternatives
- efficacious medications – genetic variations can predict which patients are likely to respond to certain medications, allowing clinicians to personalise treatment.
Limitations of pharmacogenomics
At present, there are several limitations of pharmacogenomic testing.1–4,9
- Cost – currently there is no Medicare Benefits Schedule (MBS) rebate for testing, therefore patients incur an out-of-pocket cost.
- Testing turnaround time – some results can take between five and 10 working days to reach the clinician who ordered the test. In some cases, the trial-and-error approach to dosage would be completed within this timeframe.
- Evolving science – our understanding of how genetics influences our response to drugs is incomplete. Confidence in the clinical utility of pharmacogenomic testing is slowly growing, with some parts of the world further advanced than others.
- Lack of compelling evidence from clinical trials.
Current practice in Australia
While pharmacogenomics seem to offer the ability to improve patient care (and hence therapeutic outcomes), the clinical adoption of pharmacogenomic interventions has been slow.
While many of the drugs commonly prescribed in general practice (eg warfarin, fluoxetine) are influenced by genetic variation, there is currently no clear recommendation in Australia about the use of pharmacogenomic testing.
International guidelines exist about the potential use of pharmacogenomic testing;10 however, there is limited evidence from randomised controlled trials of the clinical utility and cost effectiveness of using pharmacogenomics to tailor prescribing, especially in primary care.1,9
Resources for general practitioners
Centre for Genetics Education, Pharmacogenetics
Centre for Genetics Education, Fact sheet 21: Pharmacogenetics/pharmacogenomics
National Library of Medicine, What is pharmacogenetics?