Real-time platelet P2Y(12) receptor occupancy as a promising pharmacodynamics biomarker for bridging the gap between PK/PD of clopidogrel therapy.

Clopidogrel effectively inhibits platelet aggregation in response to ADP by irreversibly binding to the platelet P2Y(12) receptor through its active metabolite. However, the observed discrepancies between the pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel present substantial challenges in individualizing of antiplatelet therapy. To address these challenges, a robust liquid chromatography-tandem mass spectrometry method has been developed to facilitate the real-time assessment of platelet P2Y(12) receptor occupancy. This method has been validated in animal models, providing a reliable link between individual PK profiles and PD effects. Target receptor occupancy offers a comprehensive overview of interindividual variations in clopidogrel metabolism, regulation of P2Y(12) receptor expression, and platelet turnover. Moreover, it directly correlates with the inhibitory effect on platelet aggregation. The levels of platelet P2Y(12) occupancy accurately reflect the extent of clinical factors influencing the PD of clopidogrel, including dosage, drug-drug interactions (DDI), and type 2 diabetes mellitus (T2DM). As a normalized metric, platelet P2Y(12) occupancy not only serves potential as a diagnostic tool for personalized clopidogrel therapy but also aids in elucidating the role of the P2Y(12) signaling pathway in cases of abnormal on-treatment platelet reactivity.