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The genetic basis underlying variation in drug response among individuals has become evident with the introduction of modern analytical methods for the analysis of gene sequence and expression. The goal of pharmacogenetics is to stratify drug therapy into groups of individual patients based on their genetic makeup. Additional factors such as the environment, diet, age, lifestyle, and state of health can influence a person's response to medicine. An understanding of an individual's genetic makeup is thought to be the key to drug selection, drug design, and dosage regimen development. Greater efficacy and safety in drug therapy is based on stratification of patients into groups based on their relevant phenotypes (Phillips et al, 2001; Mancinelli et al, 2000). Pharmacogenetics is the study of the genetic basis of interindividual patient variability in the response to drug therapy. Pharmacogenetics allows for individualization of drug therapy. In contrast, pharmacokinetics provides a means for estimating kinetic parameters of the drug absorption, distribution, metabolism, and excretion in various population subgroups and then applying the information to drug therapy for the average patient.

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Pharmacogenomics is closely related to pharmacogenetics and is considered to be an equivalent or overlapping field. Pharmacogenomics involves study of the role of genes and their genetic variations (DNA, RNA level) in the molecular basis of disease and the resulting pharmacologic impact of drugs on that disease. Pharmacogenomics is sometimes defined to include drug design aimed at variants of a pharmacologic target. Pharmacogenetics and pharmacogenomics are both important disciplines involved in the study of genes that code for drug-metabolizing enzymes (see Chapter 11), drug receptors (see Chapter 19), drug transporters, and ion channels or efflux systems (see Chapter 13). Many of the above are relatively new factors involved in determining how genetic variation contributes to diversity in the response to drugs, including the ultimate fate of the drug and its ability to exert a therapeutic response without undue side effects.

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Application of pharmacogenetics to pharmacokinetics and pharmacodynamics helps in development of models that predict an individual's risk to an adverse drug event and therapeutic response. With some drugs, pharmacogenetics allows the recognition of subgroups or strata based on differences in genetic makeup in drug receptor sequences and are therefore characterized by predictable changes in pharmacodynamic response to drugs. Understanding the genetic and molecular differences in disease etiology, individual pharmacokinetics, and drug mechanism produce insight on how a patient will respond to a given drug. For example, the monoclonal antibody Herceptin was designed to treat a subset of breast cancer patients who overexpress the HER-2 (human epidermal growth factor receptor-2) gene. Patients who lack HER-2 overexpression are considered to be nonresponders to Herceptin therapy. In the past, such differences would be apparent only after a trial-and-error period. This genetic knowledge improves our ability to select or design the proper drug for individuals suffering from a disease with a varying range of molecular defects.

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Pharmacogenetics provides justification for individualized dosing for ...

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