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Scalable system-wide CYP2C19 pharmacogenomic testing reveals excess incidence of adverse events in metabolizers receiving inappropriate prescriptions

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Existing efforts have developed recommendations to alter the use of several commonly prescribed drugs based on patient genotype Demonstrate the real world implications of the use of pharmacogenomic testing through a retrospective study of adverse events in individuals with clopidogrel prescriptions given without testing.

Methods:
We analyzed ~100K individuals from population health studies administered at multiple medical centers with medical records and clinical grade exome. We genotyped all individuals for CYP2C19 star alleles.  We identified the formulation and inferred dosage of clopidogrel by processing the prescription with GPT-4. We checked concordance with the CPIC clopidogrel use guidelines based on individual CYP2C19 genotypes (Bousman et al. 2023). We define instances of thrombosis using a comprehensive codeset based on the medical record. 

Results:
We identified 27,688 clopidogrel prescriptions given to 2,444 participants. Of these,1,283 individuals had a calculable precise daily dose. 25% of these individuals have a mismatch between the recommended clopidogrel dosage guideline based on their CYP2C19 genotype and their prescribed dose. 12% of these mismatched individuals are poor metabolizers (PM), who should not use clopidogrel at all. The remaining 88% are intermediate metabolizers (IM). PMs and IMs receiving clopidogrel are much more likely to experience thrombosis than other metabolizers. 25% of PMs experienced thrombosis after the initiation of clopidogrel, with 40% of these occurring in the first two months (vs normal metabolizers, binomial p-value = 0.001).

Conclusion:
As expected from a lack of testing and a high population frequency of pharmacogenomic variants, many patients are prescribed doses of clopidogrel that are too high given their subsequently derived pharmacogenomic information. There is at least a 38% excess of adverse events (as measured by thrombosis) in this group. At minimum, this testing could prevent 1 thrombosis event per every ~30 people prescribed clopidogrel, demonstrating tangible benefits of population-based pharmacogenomic testing. 

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