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CYP2C19 and Clopidogrel Efficacy

A series of articles in the New England Journal of Medicine and the Lancet this week report on the clinical impact of deficiency alleles of CYP2C19. This cytochrome P450 is required for activation of the anti-platelet drug, clopidogrel. Deficiency alleles are common in the population and result in decreased activity of the P450 enzyme. Subjects who carried a deficiency allele(s) in these studies had worse clinical outcomes than did subjects with functional alleles. These findings make the case (again) that drug dosing often needs to be tailored to account for genetic differences between patients. We are used to thinking about genetic factors in the susceptibility to and causation of disease. Now we must increasingly think about them in a therapeutic context as well. Depending on the drug, some patients may need a lower or higher dose. In some patients, a drug may have no benefit or be highly toxic. The key is to make this determination in a timely way so that patients receive maximum benefit with minimum risk. Ideally, we would link results from laboratory genetic analysis with data on the likely phenotypic consequences and present this information in a useful way to the clinician at the "sweet spot", that is when a decision about choosing a drug or dosage is being made.