Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes.

Background: Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown.

Cytochrome p-450 polymorphisms and response to clopidogrel.

Background: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function.

Methods: We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects.

4th US FDA-Drug Information Association pharmacogenomics workshop, held 10-12 December, 2007.

The 4th US FDA/Industry workshop, in a series on Pharmacogenomics, was on 'Biomarkers and Pharmacogenomics in Drug Development and Regulatory Decision Making' and was held on December 10-12, 2007 in Bethesda, MD, USA, with clear objectives to continue the dialogue that began in 2002 for enabling the use of biomarkers and pharmacogenomics in drug development and regulatory decision-making. This brief commentary will highlight the major topics and outcomes discussed at this meeting that was jointly sponsored by the FDA, The Pharmacogenomics Working Group (PWG), The Pharmaceutical Research and Manufacturers of America (PhRMA), The Biotechnology Industry Organization (BIO) and The Drug Information Association (DIA).

Third Santorini conference pharmacogenomics workshop report: "Pharmacogenomics at the crossroads: what else than good science will be needed for the field to become part of Personalized Medicine?".

This workshop discussed the use of pharmacogenomics knowledge in clinical practice. It was organized in three sections: educational needs, definition of industry as a potential trigger, and regulatory aspects. Regarding pharmacogenomics education, it appears that this is truly lacking, except for patients, who are becoming increasingly educated thanks to the media.

Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport.

Background: Drug metabolism is a multistep process by which the body disposes of xenobiotic agents such as therapeutic drugs. Genetic variation in the enzymes involved in this process can lead to variability in a patient's response to medication.

Methods: We used molecular-inversion probe technology to develop a multiplex genotyping assay that can simultaneously test for 1227 genetic variants in 169 genes involved in drug metabolism, excretion, and transport.

Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System.

The combined effects of multiple polymorphisms in several drug-metabolizing enzyme and transporter genes can contribute to considerable interindividual variation in drug disposition and response. Therefore, it has been of increasing interest to generate scalable, flexible and cost-effective technologies for large-scale genotyping of the drug-metabolizing enzyme and transporter genes. However, the number of drug-metabolizing enzyme and transporter gene variants exceeds the capacity of current technologies to comprehensively assess multiple polymorphisms in a single, multiplexed assay.

A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression.

Purpose: This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression.

Experimental Design: Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 (10-minute i.v.

The External RNA Controls Consortium: a progress report.

Standard controls and best practice guidelines advance acceptance of data from research, preclinical and clinical laboratories by providing a means for evaluating data quality. The External RNA Controls Consortium (ERCC) is developing commonly agreed-upon and tested controls for use in expression assays, a true industry-wide standard control.

Precision profiling and components of variability analysis for Affymetrix microarray assays run in a clinical context.

Although gene expression profiling using microarray technology is widely used in research environments, adoption of microarray testing in clinical laboratories is currently limited. In an attempt to determine how such assays would perform in a clinical laboratory, we evaluated the analytical variability of Affymetrix microarray probesets using two generations of human Affymetrix chips (U95Av2 and U133A). The study was designed to mimic potential clinical applications by using multiple operators, machines, and reagent lots, and by performing analyses throughout a period of several months.

Pharmacogenomic biomarkers.

Pharmacogenomic biomarkers hold great promise for the future of medicine and have been touted as a means to personalize prescriptions. Genetic biomarkers for disease susceptibility including both Mendelian and complex disease promise to result in improved understanding of the pathophysiology of disease, identification of new potential therapeutic targets, and improved molecular classification of disease. However essential to fulfilling the promise of individualized therapeutic intervention is the identification of drug activity biomarkers that stratify individuals based on likely response to a particular therapeutic, both positive response, efficacy, and negative response, development of side effect or toxicity.