Pharmacogenomics

Pharmacogenomics is an emerging field that looks at how genetic variations influence drug effects in individuals. Genetic variations can lead to differences in drug absorption, distribution, metabolism, and excretion (sometimes referred to as ‘ADME’). Variations in ADME processes can cause significant differences in drug exposure between individuals, translating into differences in efficacy and adverse effects.

In some cases, pharmacogenetic testing may be used to inform prescribing practices and individualise medicine use. The potential benefits include enhanced efficacy of prescribed therapies, reduced adverse drug reactions, and reduced drug wastage. A report commissioned by the Australian Centre for Health Research estimated that pharmacogenetic testing could save the Australian healthcare system over $1 billion annually.

Genes associated with altered drug responses include those that code for drug-metabolising enzymes, drug transporters, and human leukocyte antigen (HLA).

Drug-metabolising enzymes

The cytochrome P450 family of enzymes plays a major role in drug metabolism. Cytochrome P450 3A4 is involved in the metabolism of around 55% of prescription drugs, while CYP2D6 or CYP2C19 are involved in the metabolism of around 25% of prescription medicines. However, these enzymes are highly polymorphic, which can cause significant inter-individual differences in drug effects.

In terms of drug response, genetic variations can result in the following phenotypes:

• Poor metabolisers (i.e. have absent or markedly reduced enzyme);
• Intermediate metabolisers (i.e. have reduced enzyme);
• Extensive metabolisers (also referred to as “normal” metabolisers); and
• Ultra-rapid metabolisers (i.e. have high enzyme activity).

Codeine and CYP2D6

Codeine is an interesting example of how polymorphisms can have serious implications for a patient. For codeine to exert its opioid activity, it must be converted to its active metabolite, morphine. This reaction is catalysed by CYP2D6. Patients who are poor metabolisers will have a poor response to codeine. Conversely, patients who are extensive metabolisers or ultra-rapid metabolisers are at a greater risk of experiencing side effects. This is due to a greater conversion of codeine to morphine, which has a 200-fold greater affinity for the mu-opioid receptor. In these patients, serum morphine levels may be much higher than expected, and opioid toxicity is more likely to occur, even at commonly used doses.

Pharmacokinetic studies have found that the use of codeine in people defined as poor metabolisers leads to a 96% lower morphine exposure compared to normal metabolisers. These individuals also showed no difference in analgesia for codeine compared to placebo. Ultra-rapid metabolisers had a 45% higher exposure to morphine compared to normal metabolisers. These patients may be more likely to experience toxicity, even at low codeine doses.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that codeine be avoided in patients who are CYP2D6 ultrarapid metabolisers to avoid severe toxicity. They also recommend avoiding codeine in patients who are poor metabolisers due to the risk of poor effect. Where an alternative opioid is required, tramadol should be avoided as this agent also requires CYP2D6 for conversion to its more active metabolite.

The prevalence of different CYP2D6 phenotypes varies considerably according to ancestral background. On average, it is estimated that around 1-2% of people are ultra-rapid metabolisers, and around 5-10% of people are poor metabolisers. People of North African, Ethiopian and Arab backgrounds are more likely to be ultra-rapid metabolisers, with a reported prevalence of up to 28%.

Cytochrome P450 and depression

The management of depression can be challenging, with 50% of patients not responding to their initial antidepressant and less than 50% of patients achieving remission within 12 months of starting drug therapy. Part of this issue may be related to cytochrome P450 polymorphisms.

Two main enzymes are involved in the metabolism of antidepressants, CYP2D6 and CYP2C19. One retrospective study investigated the impact of cytochrome P450 polymorphisms on health resource utilisation in patients with anxiety and depression. The authors found that patients prescribed a medication not aligned with their pharmacogenetic test results had 69% more healthcare visits than patients whose therapy was aligned with their pharmacogenetics. These patients also had three times more medical absence days and four times more disability claims.

The potential impact of these findings is significant. One Australian study found that a quarter of people taking antidepressants were taking one that did not align with their CYP2D6 and CYP2C19 genotypes. These patients were also found to be more likely to switch between antidepressants, which is suggestive of poor therapeutic effects or adverse effects.

Thiopurine methyltransferase

Thiopurine methyltransferase (TPMT) is an enzyme that is crucial for the metabolism of thiopurines. Individuals with an inherited deficiency of this enzyme are at higher risk of adverse effects when treated with a thiopurine.

Profound deficiency of TPMT is found in around 0.3% of the population. These patients may develop severe myelosuppression when treated with usual doses of thiopurines. Around 11% of the population are carriers for this deficiency and may also have some degree of reduced tolerance to thiopurines. The Australian product information recommends testing patients for TPMT activity before starting mercaptopurine, azathioprine, and tioguanine.

Drug transporters

Organic anion-transporting polypeptides (OATP) are a family of transporters that move a wide range of endogenous and exogenous organic compounds. These transporters have a wide tissue distribution and play a role in drug uptake into various tissues, including hepatic uptake prior to drug elimination.

OATP1B1 and simvastatin

The SLCO1B1 gene provides instructions for making the protein, OATP1B1. The OATP1B1 protein is mainly found in the liver and plays an important role in the hepatic elimination of many compounds, including some drugs.

Inherited polymorphisms in the SLCO1B1 gene that lead to reduced function of OATPB1 have been associated with statin-induced myopathy. This is due to reduced hepatic uptake of the statin, which leads to higher plasma levels. Simvastatin is particularly affected by this polymorphism. The CPIC recommend that patients with decreased or poor metaboliser phenotypes should receive a lower dose of simvastatin or be prescribed an alternative statin.

Human leukocyte antigen

Variations in HLA genotype can be used to predict the likelihood of immune-mediated reactions, some of which can be severe and life-threatening.

For example, it is recommended to test for HLA-B*5701 status prior to initiating abacavir therapy. Patients who test positive have a significantly higher risk of hypersensitivity reactions. These reactions can present with symptoms similar to pneumonia, bronchitis or pharyngitis, influenza-like illness, or gastroenteritis.

Some examples of drugs that may be affected by gene variants are shown in Table 1.

Table 1. Drugs affected by gene variants

Abbreviations: AGEP, Acute Generalized Exanthematous Pustulosis; DRESS, Drug Rash with Eosinophilia and Systemic Symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Phenoconversion

Additional factors may need to be considered when interpreting pharmacogenetic results due to phenoconversion.

Phenoconversion refers to the mismatch between an individual’s genotype and phenotype, i.e. their actual drug metabolising capacity differs from what genetic testing predicts. This could be related to a range of factors, such as drug interactions.

Many medications have significant effects on metabolising enzymes. For example, a patient with a genotype for normal codeine metabolism may be converted to a poor metaboliser if codeine is co-administered with a strong inhibitor of CYP2D6 (e.g. terbinafine).

Some examples of agents known to inhibit and induce major drug metabolising enzymes are shown in Table 2.

Table 2. Medications associated with phenoconversion

The extent to which these agents impact drug metabolism will depend upon the dose administered and the duration of therapy. For enzyme-inhibiting drugs with a long half-life and high affinity for drug-metabolising enzymes, their effects can persist for many days after their last dose. For example, phenoconversion following chronic fluoxetine therapy is reported to persist for six weeks after discontinuation.

Other factors have also been implicated in phenoconversion. These include advanced age, frailty, obesity, cancer, inflammation, smoking, alcohol, and vitamin D exposure. However, further study of the impact of these factors is required.

Summary

Genetic variations have been implicated in an increased susceptibility to adverse reactions and reduced therapeutic efficacy. Pharmacogenetic testing may offer a means of individualising drug therapy to optimise both drug efficacy and tolerability. Unfortunately, high-level evidence for pharmacogenetic testing currently exists only for a relatively small number of genes.

The Royal College of Pathologists of Australia maintains a summary of drugs and their evidence for pharmacogenetic testing.