CHAPTER 29 Pharmacogenomics
I. Introduction
A. Pharmacogenomics is the study of how interindividual genetic variations affect the response to drug therapy, including the influence of these variations on drug disposition (pharmacokinetics) and desirable or undesirable drug effects (pharmacodynamics). The term pharmacogenetics is closely related to pharmacogenomics, and the terms are often used interchangeably.1
B. There are small variations in genetic sequencing among humans. Genetic polymorphisms are DNA sequencing variations that occur with at least a frequency of 1% in the population; polymorphisms are responsible for significant alterations in the way a given person responds to a given drug. The effects may be pharmacokinetic or pharmacodynamic in nature; examples are given in the following review.
1. Pharmacokinetic effects: Several genetic polymorphisms affecting drug metabolism via changes in enzymatic activity or transport proteins have been identified. Well-known examples include genetically-induced alterations in the activity of cytochrome P-450 (CYP) 2D6, CYP 2C19, and thiopurine methyltransferase. Many common drugs are affected by such alterations, including warfarin, codeine, antiarrhythmic agents, antidepressants, phenothiazine antipsychotics, and thiopurines such as mercaptopurine and azathioprine.
2. Pharmacodynamic effects: Identifying expression of certain genetic traits within the context of a disease may result in more specifically targeted drug therapy with improved response rates and lowered risk for toxicity. Targets are often cellular receptors or signal transduction modulators. A well-known example is the development of the drug trastuzumab (Herceptin) and its activity in cancers (particularly breast cancer) where the over-expression of the ERBB2 (HER2/neu) oncogene is present in the tumor. Other examples include the recent findings that certain human leukocyte antigen (HLA) expressions predispose some patients to serious hypersensitivity reactions of specific medications. HLA proteins play a role in recognizing foreign substances in the body and in the subsequent immune responses. Examples of drugs where HLA subtype expression plays a role in hypersensitivity include abacavir, allopurinol, carbamazepine, and phenytoin. Testing individuals for the expression of these HLA subtypes before selecting drug therapies may prevent serious adverse consequences in susceptible individuals. Certainly, genetic differences may also account for the presence of certain traits or diseases that may affect pharmacodynamic responses to drugs. Examples include Factor V Leiden mutations, which may predispose female patients with the mutation to be at risk of thromboembolism while taking oral contraceptives.
II. Benefits of Identifying Pharmacogenomic Variables
The field of pharmacogenomics is in its infancy. However, important and tangible recommendations for personalized prescribing are beginning to emerge. Pharmacogenomic variables are now identified for a few commonly prescribed drugs. Recommendations regarding laboratory testing and prescriber actions are now incorporated into the official prescribing literature for these drugs (Table 29-1). For other drugs, recommendations are not yet defined (Table 29-2). Pharmacogenomics is a rapidly changing discipline, and many factors, including health care costs, patient preferences, and the overall health of the patient will ultimately influence the individualization of any therapy.1
A. Benefits that can be derived via better understanding of pharmacogenomics:
1. Identify populations at risk for significant allergy or toxicity; avoid risky medications in populations in which risk outweighs benefit
2. Potential for greater overall safety in the use or dosing of a particular drug, allowing drugs to remain marketed rather than pulled from market for safety
3. Ability to individualize drug therapy, increasing disease response rates via appropriate drug selection
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