Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 4

Linking Drug Responses to Genomic Variability: the Pharmacogenetics Research Network

Dan M. Roden, M.D.
Professor of Medicine and Pharmacology
Director, Oates Institute for Experimental Therapeutics
Assistant Vice-Chancellor for Personalized Medicine
Vanderbilt University School of Medicine

The vision of a “personalized” approach to drug therapy, based on genetic markers, has had considerable exposure in the lay and scientific press. Indeed, pre-prescription genotyping to select among drugs or among dosages are part of some clinical practices. Genotyping for thiopurine methyltransferase deficiency in acute lymphocytic leukemia therapy is an example. In addition, advances in clinical pharmacogenetics have been important in improving the drug development process. Discovery of CYP2D6 variants conferring the poor metabolizer phenotype has been valuable not only to understand individual variability in plasma drug concentrations and response, but also to allow early identification of new chemical entities that use this pathway, and that therefore may display wide individual variability in responses.

The Pharmacogenetics Research Network (PGRN) was established in 2000 with the mission of advancing our knowledge of the genetic basis for variable drug responses. The major funder has been NIGMS, with contributions by other institutes, notably NHLBI. Data generated by individual sites is deposited at the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), a database established with the goal of linking drug, genetic variant, and drug response data generated by PGRN and other investigators in the field. Work at individual PGRN sites has focused on specific therapeutic areas (cancer, asthma, arrhythmias, etc), or families of key drug response molecules (drug metabolizing or transport proteins). Types of drug responses studied include both adverse drug reactions (rare and common; on- and off-target), as well as predictors of efficacy or failure of response. Strategies at individual sites vary by the nature of the specific problem being addressed, and a common evolution at many sites has been a movement from individual gene variants to interrogation of biologic pathways and whole genome approaches to study the problem of variability in drug response. In addition, network sites have organized along common theme areas to move the field as a whole forward, to generate larger working groups, and to highlight, define, and address challenges in implementing a pre-prescription genotyping view of future therapeutics: examples of theme areas include serious adverse drug reactions, cancer pharmacogenomics, heart/lung pharmacogenomics, and statistical methods. This talk will highlight approaches being taken by individual sites and by the network as a whole to advance science in the field, thereby ultimately enabling a vision of individualized medicine.

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