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Genetic influences on drug response can be divided into several categories:

  1. Altered pharmacokinetics (ie, drug absorption, distribution, tissue localization, biotransformation, and excretion). Examples include genetic polymorphisms in cytochrome P450 oxidase, dihydropyrimidine dehydrogenase, thiopurine methyltransferase enzyme, and uridine diphosphate glucuronosyltransferase enzyme.

  2. Altered pharmacodynamics (ie, the effect of a drug at its therapeutic target and at other non-target sites). Genetic variations can modulate drug response by affecting the drug target itself or one of the downstream components in the target’s mechanistic pathway. An example is the effect of polymorphisms in the gene encoding the vitamin K epoxide reductase complex on response to warfarin.

  3. Effect on idiosyncratic drug reactions. An idiosyncratic reaction is an adverse drug reaction that cannot be anticipated based on the known drug target. Examples include the association of HLA-B*5701 with a hypersensitivity reaction to the antiretroviral nucleoside analog abacavir, and the association between HLA-B*5801 and life-threatening hypersensitivity reactions to allopurinol.

  4. Effect on disease pathogenesis (ie, certain genetic variation or aberration [eg, somatic mutation]) can influence a disease pathogenesis by altering the disease severity or the response to specific or targeted therapy. For example, vemurafenib, an inhibitor of kinase BRAF, significantly improves survival in patients with unresectable or metastatic melanoma with the somatic V600E mutation in the BRAF gene. Most of the predictive biomarkers (eg, expression of PD-L1 or HER2, somatic mutations in EGFR, KRAS, or IDH1/2) for hematologic and oncologic drugs are regulatorily approved under companion diagnostics. Another example is that patients who are deficient in glucose-6-phosphate dehydrogenase must avoid certain oxidizing drugs (eg, rasburicase) because they can cause severe hemolysis.

Pharmacogenetic testing can help in the selection of certain drugs and their dosages. Table 40–2 lists drugs for which genetic testing has been mandated or recommended.

Table 40–2.Selected pharmacogenetic tests: clinical relevance.1

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