Basic principles of pharmacogenetics and individualised medicine

Definition

Pharmacogenetics studies how genetic variation affects individual drug response - efficacy, dosing requirements, and adverse effect risk - increasingly incorporated into routine prescribing decisions for specific high-risk drug-gene pairs
A growing number of drug-gene pairs now have clinical prescribing guidelines (e.g. from the Clinical Pharmacogenetics Implementation Consortium, CPIC), reflecting the maturation of pharmacogenetics from a research field to routine clinical practice for specific drugs

Genetic variation most commonly affects drug-metabolising enzymes (particularly cytochrome P450 enzymes - CYP2D6, CYP2C19, CYP2C9) or drug targets/receptors, altering how quickly a drug is metabolised (poor, intermediate, extensive, or ultra-rapid metaboliser phenotypes) or how the body responds to a given drug concentration

Classic examples: CYP2C19 genotype affects clopidogrel activation (poor metabolisers get reduced antiplatelet effect); *HLA-B15:02 predicts severe cutaneous adverse reactions (Stevens-Johnson syndrome) to carbamazepine, particularly relevant in some Asian populations; TPMT/NUDT15 genotype predicts thiopurine (azathioprine) myelosuppression risk; CYP2D6** genotype affects codeine's conversion to morphine (ultra-rapid metabolisers risk opioid toxicity, poor metabolisers get inadequate analgesia)
Clopidogrel resistance, carbamazepine-induced Stevens-Johnson syndrome, thiopurine-induced myelosuppression, codeine metabolism variability, warfarin dosing (CYP2C9/VKORC1)

Pre-emptive or reactive pharmacogenetic testing for a specific high-risk drug-gene pair can guide dose selection or avoidance before prescribing, particularly for drugs with a narrow therapeutic index or a risk of severe idiosyncratic reaction
Where testing is not available/practical, awareness of population-level variation in metaboliser phenotype frequency can still inform empirical prescribing caution in specific higher-risk scenarios

Pharmacogenetic testing is most valuable for drugs with serious, genetically-predictable toxicity or efficacy variation and a validated actionable guideline - it is not yet routine for the majority of prescribed drugs, and its clinical use should be targeted to established high-value drug-gene pairs rather than applied indiscriminately

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