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    Pharmacogenomics: Improving Dosing and Decreasing Adverse Events

    Pharmacogenomics is the science of determining how genetic variability influences physiological responses to drugs, from absorption and metabolism to pharmacologic action and therapeutic effect. With increasing knowledge of the molecular basis for a drug’s action has come the recognition of the importance of an individual’s genetic makeup in influencing how he or she may respond to a drug.

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    Genetic variants in drug metabolizing enzymes can have a significant effect on the way a person responds to a drug. They can speed up or slow down enzymatic activity, or even inactivate an enzyme. In some patients, known as rapid metabolizers, drugs are metabolized too quickly. As a result, the average dose of the drug may be broken down too quickly to be effective, and a higher dose may be needed. Conversely, where the metabolite of the drug is active, as in the case of codeine (see below), rapid metabolism may lead to excessive accumulation of the active metabolite, which may result in toxic levels. In slow metabolizers, a drug administered at the recommended dose can accumulate due to such slow metabolism, potentially reaching toxic levels in the patient’s system and leading to adverse reactions. Such patients may require a smaller dose. In conjunction with other factors, pharmacogenomics offers the potential to enable doctors to identify the patients who are rapid or slow metabolizers of certain drugs and to adjust dosing accordingly to achieve both effective and safe treatment.

    • Rapid metabolizers may break down a drug too quickly and require higher doses.
    • Slow metabolizers may build up toxic levels of the drug and require smaller doses.

    Clinical Applications of Pharmacogenomics
    Warfarin (Coumadin and generics), an anticoagulant, is a recent example of the clinical use of pharmacogenomics to improve dosing. Warfarin has a narrow therapeutic window and a wide range of inter-individual variability in response, requiring careful clinical dose adjustment for each patient. Genetic variants in the warfarin target, the vitamin K epoxide reductase (VKORC1), as well as the warfarin metabolizing enzyme, cytochrome P450 2C9 (CYP2C9), influence the variation in patient response. Patients with certain variants of these genes eliminate warfarin more slowly and typically require lower warfarin doses. In those individuals, a traditional warfarin dose would more likely lead to an elevated International Normalized Ratio (INR), a longer time to achieve a stable warfarin dose, and a higher risk of serious bleeding events during the induction or dose-titration period of warfarin therapy. (FDA News)

    Another recent example involves ultrarapid metabolizers of codeine, who have multiple copies of the gene for cytochrome P450 2D6 (CYP2D6), the enzyme that converts codeine into morphine, its active metabolite.

    Tests to identify the three genetic polymorphisms for warfarin, codeine, and carbamazepine described above are commercially available.


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