Introduction to pharmacogenomics

Pharmacogenomics, also known as pharmacogenetics, explores the ways in which a person’s genome contributes to well-established variations in different people’s responses to certain drugs.

Pharmacogenomic testing can guide prescribing decisions to improve therapeutic effectiveness and prevent adverse drug reactions. Pharmacogenomic insights have also informed the identification of novel therapeutic targets and have supported the repurposing of existing drugs for novel applications.

Watch the short animation below for a helpful overview of pharmacogenetics and the significance of its role in healthcare.

Inter-individual variability in response to therapeutics is well recognised. Causes are multifactorial, and many are routinely considered in daily clinical care (such as weight, comorbidities and drug-drug interactions). Genetic variation is known to contribute to this inter-individual variation in response to therapeutics, but this knowledge is currently under-utilised in clinical practice.

Genetic variation influences both what the body does to the drug (known as pharmacokinetics) and what the drug does to the body (known as pharmacodynamics). Consequently, certain genetic variants have come to be associated with the risk of adverse drug reactions or inefficacy.

Drug-gene pairing

There are a growing number of drug-gene pairs (see table 1 below) in which awareness of genetic variation could lead to a change in prescribing behaviour. There are pharmacogenetic dosing guidelines on the drug labels of many commonly prescribed groups of medicines – including analgesics, antiplatelets, antibiotics, chemotherapy agents, statins, antidepressants and proton pump inhibitors. Given the breadth of medicines for which genetic dosing guidelines exist, pharmacogenomics has relevance in a broad range of clinical specialities – including cardiology, anaesthesia, oncology, psychiatry, neonatology, stroke medicine and primary care.

The use of pharmacogenomic tests for inherited (constitutional, or germline) and acquired (somatic) genetic variants is well established in oncology. The case for using genomic tests to prevent severe adverse drug reactions is particularly strong for medicines with a narrow therapeutic index, such as chemotherapy.

For example, about one-fifth of patients treated with fluoropyrimidines suffer from severe adverse drug reactions that can result from impaired metabolism. The gene DPYD encodes a liver enzyme that metabolises most of the active drug into non-cytotoxic metabolites. Some individuals are homozygous or heterozygous for rare, catalytically inactive DPYD alleles. The association between these variants and toxicity is very well established, and pharmacogenomic testing is now used to guide and adjust the dosing of fluoropyrimidines in clinical practice.

Several clinically actionable pharmacokinetic biomarkers are associated with the cytochrome P450 (CYP) liver enzyme superfamily. The enzymes encoded by the genes CYP2D6, CYP2C19, CYP3A5 and CYP2C9 metabolise many commonly prescribed medicines, including warfarin, clopidogrel, antidepressants and analgesics, and are highly polymorphic (table 1). The plasma concentration of a drug (or its metabolites) can vary significantly between patients because of heterogeneity in the activity of these enzymes, which in turn can be predicted by genomic testing for underlying polymorphisms – from missense single nucleotide variants to truncating stop-gain variants and copy number variants.

Table 1: Examples of clinically actionable constitutional (germline) drug-gene pairs

There are two main organisations that create international consensus guidelines for prescribing based on pharmacogenomic variation:

• The Clinical Pharmacogenetics Implementation Consortium publishes genotype-based drug guidelines to help clinicians understand how available genomic test results could be used to optimise drug therapy.
• The Dutch Pharmacogenetics Working Group (DPWG) is a multidisciplinary organisation that includes clinical pharmacists, physicians, clinical pharmacologists, clinical chemists, epidemiologists and toxicologists. The DPWG aims to develop pharmacogenomics-based therapeutic recommendations and to assist drug prescribers and pharmacists by integrating the recommendations into electronic systems for drug prescription and automated medication surveillance.

The guidelines and databases curated by these organisations (see the resources section below) can help researchers and clinicians apply a uniform nomenclature to genes and alleles or appraise the analytic and clinical validity and discrimination profiles for tests or test panels.

There is good evidence to support genotype-guided prescribing for a range of medicines, and the fall in the cost of genomic sequencing allows for greater use in clinical practice. Despite this, there are remaining barriers to prospective pharmacogenomic testing, as evidenced by the lack of clinical implementation across the UK.

Currently, there are only five drug-gene pairs in which testing occurs on a relatively routine basis:

• azathioprine: TPMT and NUDT15;
• abacavir: HLA-B;
• fluoropyrimidines: DPYD;
• carbamazepine: HLA-A and HLA-B; and
• aminoglycoside antibiotics: MT-RNR1.

NICE has recently produced draft guidance for CYP2C19 to guide antiplatelet therapy following ischaemic stroke, though testing is not widely available in the UK at the moment.

It is likely that pharmacogenomic testing will become more widespread for an increasing number of medicines within the NHS over the next decade. This will require academics and clinicians to overcome a number of barriers and will necessitate the evolution of the UK pharmacogenomic testing infrastructure (which will involve pre-emptive or point-of-care testing and the development of IT solutions to support pharmacogenomics within clinical practice).

For clinicians

• British Pharmacological Society and Royal College of Physicians: Personalised prescribing: Using pharmacogenomics to improve patient outcomes (PDF, 51 pages)
• Clinical Pharmacogenetics Implementation Consortium
• Dutch Pharmacogenetics Working Group
• Medicines Learning Portal: Pharmacogenomics (elearning resource)
• Pharmacogene Variation Consortium (PharmVar)
• PharmGKB
• PHG Foundation: Explaining pharmacogenomics (video, two minutes 16 seconds)
• The University of Chicago Center for Personalized Therapeutics
• Ubiquitous Pharmacogenomics

References:

• Relling MV and Evans WE. ‘Pharmacogenomics in the clinic’. Nature 2015: volume 526, pages 343–350. DOI: 10.1038/nature15817

For patients

• British Pharmacological Society and Royal College of Physicians: Summary extract from Personalised prescribing: Using pharmacogenomics to improve patient outcomes (PDF, 2 pages)