PROJECT SUMMARY
Gene-drug-drug interactions (GDDIs) are becoming a new frontier in Precision Medicine (PM).
Pharmacogenomics can certainly be a good predictive tool to guide drug therapies but is far from being a
deterministic measure of phenotypes. A current limitation in most of existing guidelines is their lack of provisions
to address the effect of drug combinations, co-medications and, therefore, the risk for GDDIs. Although the high
inter-individual variability in the response to clopidogrel has primarily been associated with genetic
polymorphisms, multivariate analyses suggest that additional factors (e.g., GDDIs) may contribute to the overall
between-subject variability in treatment response. However, the extent to which each of these additional factors
contributes to the overall variability, and how they are interrelated, is currently unclear. To this purpose, we
propose to derive, for the first time ever, a weighted genetic risk score system based on a genome-wide
association study in Caribbean Hispanic patients and machine learning methods. We also plan on developing a
novel semi-mechanistic population-based pharmacokinetic/pharmacodynamics (PK-PD) modeling of clopidogrel
in individuals with GDDIs with cilostazol in order to identify the clinically relevant factors affecting drug exposure
and response, which may ultimately serve as a solid basis for dosing optimization and tailoring therapies. Based
on strong preliminary data, we hypothesize that:
“The enhancing effect of cilostazol over the clopidogrel-induced anti-platelet activity in Caribbean Hispanic
patients exposed to these interacting co-medications is exclusive of those who also are CYP2C19 PMs and
CYP3A5 non-expressers”
This study is expected to provide important new information on the proportions of individuals from the Caribbean
Hispanic population who are likely to have combinations of pharmacogenomics variants and exposure to
interacting co-medications that may eventually affect their health care. Hispanics have been largely excluded
from PM initiatives, which increase dramatically the disparities in translating benefits from new findings in
pharmacogenomics to this medically underserved population, exacerbating the existing inequity in healthcare
services. Accordingly, the proposed research will expand our current understanding of the PK-PD interactions
between clopidogrel and cilostazol from a pharmacogenetics perspective. Advancing knowledge in the under-
investigated area of pharmacogenetics in minority populations will generate results that apply to personalize
antiplatelet therapy in the wider population as it moves, inevitably, toward increasing heterogeneity through
admixed genomes.
