Clopidogrel and CYP2C19: Pharmacogenetic Testing Ready for Clinical Prime Time?
Bibliographic record
Abstract
Dual antiplatelet therapy with clopidogrel and aspirin has become the mainstay of therapy for patients with acute coronary syndrome (ACS)6 undergoing percutaneous coronary interventions (PCI). Many pharmacokinetic and pharmacodynamic studies have demonstrated substantial interindividual variation in antiplatelet response with clopidogrel, a significant proportion of which is explained by the variation in plasma concentrations of the clopidogrel active metabolite. Clopidogrel is a prodrug that requires bioactivation by the highly polymorphic enzyme CYP2C19 to form the active metabolite. The growing body of literature has implicated the loss-of-function cytochrome P450, family 2, subfamily C, polypeptide 19 variant ( CYP2C19 * 2 )7 variant with an increased risk of major cardiovascular events. This evidence prompted the US Food and Drug Administration (FDA) to implement a boxed warning on the clopidogrel label describing the relationship between CYP2C19 pharmacogenetics and drug response, emphasizing the diminished effectiveness in CYP2C19 poor metabolizers. CYP2C19 pharmacogenetic testing is currently available to guide antiplatelet therapy; however, there are challenges with implementing pharmacogenetic-guided therapy in clinical practice. In this Q&A, 3 experts discuss the current state, challenges, and future direction of CYP2C19 pharmacogenetic testing for clopidogrel therapy. Can you briefly summarize the latest developments and evidence for pharmacogenetic testing in patients on clopidogrel therapy? Jean Hulot: Clopidogrel is a prodrug that requires hepatic bioactivation to generate an active metabolite with antiplatelet properties. The CYP2C19 enzyme is directly involved in this bioactivation process but its activity is genetically determined. A common loss-of-function genetic variant (named CYP2C19 * 2 ; c.681G>A; rs4244285) is associated with reduced formation of the clopidogrel active metabolite and reduced pharmacodynamic response to the drug, thus resulting in high on-treatment platelet reactivity and more frequent adverse cardiovascular events. This effect is particularly observed in homozygous carriers of the mutated allele (so-called poor metabolizers), who represent 3%–4% of Caucasian patients. …
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".