Pharmacogenomics refers to the use of genetic and genomic information to tailor pharmaceutical treatment to an individual. Combining pharmacology with genomics enables us to use information about a person’s genome to identify the most effective drug and dosage for them or minimise side effects.
DNA variation can affect two aspects of drug function; pharmacokinetics, or how the drug is distributed, metabolised and excreted by the body, and pharmacodynamics, the effect a drug has on its target in the body and ‘off-target’ effects of drugs.
Some examples of pharmacogenomics in current prescribing are as follows:
- Abacavir, an antiretroviral used in the treatment of HIV/AIDS, causes a severe hypersensitivity reaction in around 5% of people, which in some cases is life threatening. These individuals have a specific DNA variant of the HLA-B gene, HLA-B5701, which encodes for a protein playing a crucial role in the immune system. Prior to prescribing Abacavir to any patient, testing for this allele is required, which had dramatically reduced the occurrence of this hypersensitivity reaction. This test is not on the NHS Genomic Test directory and should be requested through local hospital requesting systems.
- Fluoropyrimidine chemotherapies (eg, capecitabine, 5-fluorouracil, tegafur) can be accompanied by drug toxicity and adverse reaction in some patients, due to decreased activity of the metabolic enzyme dihydropyrimidine dehydrogenase (DPD). DPD is encoded by the DPYD gene and some inherited variants in this gene affect DPD activity. Patients with these variants are not able to metabolize fluoropyrimidines at normal rates and patients have an associated risk of severe drug toxicity. Screening for DPYD variants can identify those at potential risk and dosing regimes can be modified accordingly. This test is on the NHS Genomics Test directory and can be ordered through the C&S GLH by the patients’ oncology team. Test directory codes relate to different cancer types and are found in the National genomic test directory for cancer.
- Mavacamten (CAMZYOS) is offered as a third-line medical therapy for the treatment of Hypertrophic cardiomyopathy (HCM), a genetic disorder of cardiac myocytes leading to left ventricular hypertrophy in the absence of hypertension, pressure overload or infiltrative states. Mavacamten is metabolised through the liver, and genetic variation in hepatic enzymes can affect the rate of metabolism of the drug. CYP2C19 genotyping is required to guide mavacamten therapy and dosing. CYP2C19 metabolizer phenotype should be available prior to commencing treatment. CYP2C19 genotyping is on the NHS Genomics Test directory (R454) and is currently ordered through the Bristol Genomics Laboratory by the patients’ cardiology team.
- Aminoglycosides are broad-spectrum bactericidal antibiotics, such as gentamicin, amikacin, tobramycin and neomycin. There is a narrow therapeutic window for aminoglycosides and their use can result in toxicity, including nephrotoxicity and ototoxicity, which can result in permanent hearing loss. Some evidence suggests an association between mitochondrial mutations (particularly the m.1555A>G mutation) and an increased risk of ototoxicity. Healthcare professionals should consider genetic testing in patients, particularly in those requiring recurrent or long-term treatment with aminoglycosides. Patients with known mitochondrial mutations or a family history of ototoxicity are advised to inform their doctor or pharmacist before they take an aminoglycoside. Testing of relevant mitochondrial mutations is available on the NHS Genomics Test directory (R65.1) and can be ordered through the C&S GLH by the patients’ clinical team.
As with all genomic tests, these must be ordered by healthcare professionals, usually the clinician in charge of an aspect of the patient’s care. Tests are ordered through the National Genomic Test Directory; the majority of pharmacogenomic tests are held within the rare disease directory, expect for those that relate to cancer or cancer treatments.