Authors' objectives:

This report will provide background information on cytochrome p450 (CYP450) enzymes, genotyping applications for currently available drugs, examples of companies and products, evaluation of clinical utility, examples and the current state of evidence, regulatory issues, and cost-effectiveness analysis.

This report will also describe regulatory initiatives applicable to new drugs, but will not otherwise discuss the use of pharmacogenomics in ongoing drug development. A Technical Information section will be provided that will be useful to readers in defining genetics terminology and describing technologies.

Authors' results and conclusions: Drug efficacy and toxicity vary substantially across individuals. Because drugs and doses are typically adjusted, if needed, by trial and error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result. Various factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions. Inherited DNA sequence variation (polymorphisms) in genes for drug-metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the efficacy or toxicity of a drug. Predicting therapeutic failures or severe adverse drug reactions by genotyping for important polymorphisms in key drug-metabolizing enzymes, receptors, transporters, etc., has the potential to optimize drug choice and/or dose earlier for more effective therapy, avoid serious adverse effects, and decrease medical costs. The CYP450 family is a major subset of all drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. Some CYP450 enzyme genes are highly polymorphic, resulting in enzyme variants some of which have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzyme variants constitute one important group of drug-gene interactions influencing the variability of effect of some CYP450 metabolized drugs. Diagnostic tests to identify specific polymorphisms that may be linked to increased/reduced effect or serious adverse effects are now available. Whether or not such testing, and for which drugs, improves patient outcomes is not yet known. While genotyping for the CYP450 enzymes would only need to be done once per patient and the results could be used to consider other drugs metabolized by the same enzymes, whether or not genotyping is clinically useful would need to be determined for each drug. Even drugs of the same class may variably rely on specific CYP450 enzymes. For example, the plasma level of the selective serotonin reuptake inhibitor (SSRI) fluoxetine is significantly affected by CYP2D6 polymorphisms, whereas the SSRI sertraline appears to be little affected and may depend more upon CYP2C19 for metabolism. Additionally, different approaches to genotyping (SNPs vs. known sequence polymorphisms, single gene vs. haplotype) may result in a variety of tests to be validated, each directed toward a subset of enzymes or drugs. Appropriate outcomes for evaluation might include adverse events; days hospitalized; and time to a clinically significant, predefined change in condition using an appropriate and validated measure. Evaluating the cost of treatment, including managing adverse events, with and without genotyping may also provide useful information.

Authors' recommendations: While the potential of pharmacogenomics is intriguing for many clinical applications, it is not yet clear which are most likely to yield clinical benefit in the near future. As this field evolves and matures, and if pre-prescription testing is shown to be of clinical utility for specific drugs, it will be important to establish evidence-based guidelines for healthcare professionals delineating the most effective courses of action based on genotyping results. Because pharmacogenomic applications may be complex and multifactorial, such guidelines will be of great value for the practicing clinician.

Authors' methods: Review

Project Status: Completed

URL for project: http://www.bcbs.com/blueresources/tec/contact-tec.html

Year Published: 2004

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: BlueCross BlueShield Association

Contact Address: BlueCross BlueShield Association, Technology Evaluation Center, 225 North Michigan Ave, Chicago, Illinois, USA. Tel: 888 832 4321

Contact Name: tec@bcbsa.com

Contact Email: tec@bcbsa.com

Copyright: BlueCross BlueShield Association (BCBS)