Pharmacogenetics & Pharmacogenomics

Implications of pharmacogenomics for drug development and clinical practice

Ginsburg, GS et al., 2005. Arch Internal Med 165:2331-2336.

Abstract

Pharmacogenomics is likely to be among the first clinical applications of the Human Genome Project and is certain to have an enormous impact on the clinical practice of medicine. Herein, we discuss the potential implications of pharmacogenomics on the drug development process, including drug safety, productivity, market segmentation, market expansion, differentiation, and personalized health care. We also review 3 challenges facing the translation of pharmacogenomics into clinical practice: dependence on information technology, limited health care financing, and the scientific uncertainty surrounding validation of specific applications of the technology. To our knowledge, there is currently no formal agenda to promote and cultivate innovation, to develop progressive information technology, or to obtain the financing that would be required to advance the use of pharmacogenomic technologies in patient care. Although the potential of these technologies is driving change in the development of clinical sciences, it remains to be seen which health care systems level needs will be addressed.

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Comment

This article is a brief summary of the major areas in drug development and clinical practice likely to be impacted by pharmacogenomics.

Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications.

Bernard, S N et al., 2006.  Oncologist 11(2): 126-35.

Abstract

DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide inter-individual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity. Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT(3)-receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country's wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug-drug interactions increases.

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Comment

This review has three learning objectives, and it achieves them well. in addition to a general introduction these include understanding the four genotypes for CYP2D6 polymorphisms, the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme, and a useful listing of the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme.  Although focused on the this single enzyme and its variants, this article is a good introduction/review for other clinical important enzymes and proteins encoded by polymorphic genes.

Inheritance and drug response

Weinshilboum, R. 2003. N. Eng. J. Med. 348(6):529-537

Abstract

The promise of pharmacogenetics, the study of the role of inheritance in the individual variation in drug response, lies in its potential to identify the right drug and dose for each patient. Even though individual differences in drug response can result from the effects of age, sex, disease, or drug interactions, genetic factors also influence both the efficacy of a drug and the likelihood of an adverse reaction. This article briefly reviews concepts that underlie the emerging fields of pharmacogenetics and pharmacogenomics, with an emphasis on the pharmacogenetics of drug metabolism. Although only a few examples will be provided to illustrate concepts and to demonstrate the potential contribution of pharmacogenetics to medical practice, it is now clear that virtually every pathway of drug metabolism will eventually be found to have genetic variation. The accompanying article by Evans and McLeod expands on many of the themes introduced here. Once a drug is administered, it is absorbed and distributed to its site of action, where it interacts with targets (such as receptors and enzymes), undergoes metabolism, and is then excreted. Each of these processes could potentially involve clinically significant genetic variation. However, pharmacogenetics originated as a result of the observation that there are clinically important inherited variations in drug metabolism. Therefore, this article - and the examples highlighted - focuses on the pharmacogenetics of drug metabolism. However, similar principles apply to clinically significant inherited variation in the transport and distribution of drugs and their interaction with their therapeutic targets. The underlying message is that inherited variations in drug effect are common and that some tests that incorporate pharmacogenetics into clinical practice are now available, with many more to follow. The concept of pharmacogenetics originated from the clinical observation that there were patients with very high or very low plasma or urinary drug concentrations, followed by the realization that the biochemical traits leading to this variation were inherited. Only later were the drug-metabolizing enzymes identified, and this discovery was followed by the identification of the genes that encoded the proteins and the DNA-sequence variation within the genes that was associated with the inherited trait. Most of the pharmacogenetic traits that were first identified were monogenic - that is, they involved only a single gene - and most were due to genetic polymorphisms; in other words, the allele or alleles responsible for the variation were relatively common. Although drug effect is a complex phenotype that depends on many factors, early and often dramatic examples involving succinylcholine and isoniazid facilitated acceptance of the fact that inheritance can have an important influence on the effect of a drug. Today there is a systematic search to identify functionally significant variations in DNA sequences in genes that influence the effects of various drugs.

Journal Link | PMID

Comment

Although somewhat dated, this remains a very good introduction to medical genomics.  In addition, it reviews several of the major enzyme systems (i.e., Cytochrome P₄₅₀'s, N-acetyltransferase, thiopurine S-methyltransferase) involved in common clinical situations, and includes some population frequency data.