MRC Integrative Epidemiology Unit (IEU) Seminar Series

Title: Assessing the clinical impact of pharmacogenetic variation on phenytoin prescribing practice and patient response

Abstract:

Genetic variation in drug metabolizing pathways affects medication safety and efficacy. However, the implications of these variants for real-world patients is not well established. We conducted a retrospective study in the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, which includes 110,266 participants who were members of a large integrated healthcare delivery system for an average of 10 years and who contributed DNA for health-related research. Using Phenytoin as a model drug, we determined the effect of reduced CYP2C9 activity on dose-adjusted phenytoin blood levels, on clinically-recognized neurological side effects, and on drug prescribing behavior. We confirmed the well-known associations between CYP2C9 variation and circulating drug concentrations, and identified high rates of neurological side effects among patients with reduced drug metabolism. Most interestingly, we also identified associations between expected CYP2C9 drug metabolizing activity and likelihood of switching to alternative anticonvulsants, lowering phenytoin dose over time, and poor medication adherence. These findings suggest broad implications of pharmacogenetics in health systems, including not only pharmacokinetic and pharmacodynamic effects, but also implications for clinical prescribing practice and patient compliance. 

Biography: 

Dr. Fohner is an Assistant Professor in the Department of Epidemiology and Assistant Director of the Institute for Public Health Genetics at the University of Washington. She applies innovative big data methods to extensive electronic health record and genomic data to improve precision medicine. Her recent work has explored novel genetic variation affecting drug metabolism in understudied populations, applied unsupervised machine learning to improve phenotype definitions in sepsis, and assessed levels of evidence for translation of pharmacogenetics into clinical care. She approaches genetic epidemiology through an ELSI (ethical, legal, social implications) lens, and aims to promote equity and justice in the benefit of and access to genetic information in health settings. She is also a researcher with the Cardiovascular Health Research Unit at the University of Washington.  

All welcome