20.4 Clinical Pharmacogenomics

What Is Clinical Pharmacogenomics?

Clinical pharmacogenomics uses a patient's genotype to predict drug response and guide prescribing. The aim is to maximise efficacy and minimise serious adverse reactions by choosing the right drug and dose for the individual. The DHA Pharmacist blueprint focuses on a small set of high-impact gene-drug pairs that have changed labelling and clinical guidelines.

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CYP2C19 and Clopidogrel

Clopidogrel is a prodrug. It must be converted by CYP2C19 in the liver to its active antiplatelet metabolite. Patients who are CYP2C19 poor metabolizers (e.g. *2 or *3 loss-of-function alleles, common in East Asian populations) convert substantially less clopidogrel to the active form, producing reduced antiplatelet effect and a higher rate of stent thrombosis and recurrent cardiovascular events.

For patients undergoing percutaneous coronary intervention (PCI) with stenting for acute coronary syndrome, current CPIC and FDA guidance is to avoid clopidogrel in CYP2C19 poor metabolizers and use an alternative antiplatelet not dependent on CYP2C19 activation, such as prasugrel or ticagrelor.

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HLA-B*57:01 and Abacavir

Abacavir, an NRTI used in HIV regimens, causes a severe hypersensitivity reaction in patients carrying the HLA-B*57:01 allele. The reaction can include fever, rash, gastrointestinal and respiratory symptoms, and can be fatal on re-exposure.

• Screening is MANDATORY before starting abacavir — never prescribe without a documented negative result.
• A patient who tests positive must never receive abacavir and it must be recorded as a true allergy in the medical record.
• If abacavir is stopped for any suspected hypersensitivity reaction, never rechallenge — fatal reactions have occurred within hours of re-exposure.

This is one of the strongest pharmacogenomic associations in clinical medicine and has been adopted worldwide as a pre-prescription safety check.

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CYP2D6: Codeine and Tamoxifen

CYP2D6 is highly polymorphic. Patients fall into phenotype groups from poor metabolizer to ultrarapid metabolizer.

Codeine

Codeine is a prodrug that is converted by CYP2D6 to morphine, which provides analgesia.

• Ultrarapid metabolizers convert codeine to morphine excessively and rapidly → morphine toxicity (respiratory depression, sedation) — there are case reports of fatal toxicity in breastfeeding infants exposed via milk, so codeine is contraindicated during breastfeeding and should be avoided in children, particularly after tonsillectomy.
• Poor metabolizers produce little morphine → inadequate analgesia.

Tamoxifen

Tamoxifen is also activated by CYP2D6 to endoxifen, its most active metabolite. CYP2D6 poor metabolizers may have reduced endoxifen levels and potentially reduced benefit in oestrogen-receptor-positive breast cancer. Consider an aromatase inhibitor (in postmenopausal women) or alternative endocrine therapy when appropriate.

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HLA-B*15:02 and Carbamazepine

HLA-B*15:02 is strongly associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The allele is particularly common in Han Chinese, Thai, Malay, Filipino, and other Asian populations.

• Screen patients of Asian ancestry before starting carbamazepine (and the structurally related oxcarbazepine) when feasible.
• If positive, avoid carbamazepine unless the benefit clearly outweighs the risk.
• The same allele is associated with SJS/TEN from phenytoin and lamotrigine in some populations.

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Warfarin: CYP2C9 and VKORC1

Warfarin dosing has a strong genetic component and is one of the best-established pharmacogenomic applications in routine care.

Algorithms combining CYP2C9 and VKORC1 genotype with clinical factors (age, weight, interacting drugs) produce more accurate starting doses than empirical dosing and reduce early bleeding events.

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Thiopurines: TPMT and NUDT15

Azathioprine, 6-mercaptopurine (6-MP), and thioguanine are thiopurines metabolised in part by thiopurine S-methyltransferase (TPMT). Patients with TPMT deficiency accumulate active thioguanine nucleotides, causing severe, potentially fatal myelosuppression.

A second enzyme, NUDT15, is also relevant — NUDT15 deficiency (especially common in East Asian populations) similarly predicts severe myelosuppression.

• Test TPMT and NUDT15 activity or genotype before starting a thiopurine.
• In deficient patients, reduce dose substantially (e.g. to 10% of standard for homozygous deficient) or choose an alternative.

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Fluoropyrimidines: DPYD

5-fluorouracil (5-FU) and capecitabine are fluoropyrimidines used in colorectal, breast, and other solid tumours. They are inactivated by dihydropyrimidine dehydrogenase (DPD), encoded by DPYD. Patients with DPYD deficiency develop severe, sometimes fatal toxicity — neutropenia, diarrhoea, mucositis, hand-foot syndrome. Test DPYD before starting a fluoropyrimidine and reduce the dose (or avoid) in partial- or full-deficiency carriers.

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Quick Reference Table

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CYP2C19 Phenotype Spectrum

CYP2C19 metabolizer phenotypes are graded along a spectrum, and the exam may present intermediate rather than poor metabolizers:

• Ultrarapid metabolizer: may convert clopidogrel more rapidly, but this does not usually change practice because efficacy plateaus.
• Normal (extensive) metabolizer: standard clopidogrel dosing.
• Intermediate metabolizer (one loss-of-function allele, e.g. *1/*2): reduced activation; the evidence for switching is weaker than for poor metabolizers, but many guidelines suggest caution and consider alternatives in high-risk PCI.
• Poor metabolizer (two loss-of-function alleles, e.g. *2/*2 or *2/*3): clearly reduced active metabolite and higher stent thrombosis risk — switch to prasugrel or ticagrelor.

This spectrum explains why guidelines emphasise genotype over a binary yes/no result.

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Implementing Pharmacogenomics in Pharmacy Practice

The pharmacist's role in pharmacogenomics is growing. Practical implementation points:

• Timing: for clopidogrel after PCI, results are needed quickly — point-of-care or rapid turnaround testing is preferred; do not delay dual antiplatelet therapy while waiting; start a CYP2C19-independent agent if results are not available within a reasonable window.
• Documentation: record the genotype, phenotype, and resulting prescribing decision in the patient record so it is not lost at transitions of care.
• Patient education: explain that a genetic result is lifelong and does not need repeating, but that it only applies to the drugs in question — a CYP2C19 result does not predict response to non-CYP2C19 substrates.
• Drug-drug interactions layered on genotype: a CYP2D6 normal metabolizer on a strong CYP2D6 inhibitor (e.g. paroxetine) behaves phenocopy-wise as a poor metabolizer — check both genotype and interacting medicines before finalising a codeine or tamoxifen decision.
• Pharmacovigilance: report serious adverse drug reactions that occur despite genotype-guided prescribing, as these help refine future guidance.