Clinical trials in pharmacogenetics and pharmacogenomics: methods and applications.
Clinical and other aspects of pharmacogenetics and pharmacogenomics are discussed. Pharmacogenetics is the study of the impact of heritable traits on pharmacology and toxicology. An extension of pharmacogenetics is the discovery that genetic polymorphisms have the potential to affect a drug's action. The interplay of genotype and drug efficacy has been defined as pharmacogenomics. For most drugs, variations in patient response have until recently been considered a result of pharmacokinetic rather than pharmacodynamic differences. However, it now seems that pharmacodynamic variability in humans is large, reproducible, and usually more pronounced than pharmacokinetic variability. Some examples of the impact of pharmacogenomics on pharmacokinetics involve cytochrome P-450 isoenzymes, dihydropyrimidine dehydrogenase, and thiopurine methyltransferase; some examples of the impact on pharmacodynamics involve cholesteryl ester transfer protein, angiotensin-converting enzyme, and serotonin transporter. There are no specific statistical techniques for analyzing data from pharmacogenomic clinical trials. However, a tabulated relationship for the determination of the maximum possible gain in response rate for the highest-responding genotypic subgroup of patients is provided as an aid to determining whether it is worth having a pharmacogenomic strategy for a given drug. Ethical issues in pharmacogenomics tend to be based on the general concern that the ability to diagnose a genetic disorder before any treatment is available does more harm than good to the patient. Pharmacogenomic approaches to drug discovery and delivery have been recognized by FDA. Pharmacogenomics cannot improve the efficacy of a given drug, but it helps in selecting patients who are likely to respond well. Pharmacogenomics provides a view of drug behavior and sensitivity useful to improving the efficacy of drug development and utilization.
Rioux
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prioux@usa.net
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins; D002986:Clinical Trials as Topic; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000737:chemistry; D042943:Dihydrouracil Dehydrogenase (NADP); D004335:Drug and Narcotic Control; D016678:Genome; D006023:Glycoproteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010088:Oxidoreductases / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D010597:Pharmacogenetics; D050486:Serotonin Plasma Membrane Transport Proteins
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D007703:Peptidyl-Dipeptidase A