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ADP-mediated aggregation as a pharmacodynamic assay underestimates the antithrombotic activity of elinogrel, a competitive, reversible P2Y12 inhibitor, relative to clopidogrel
Abstract number: PP-TH-027
Conley1 P.B., Andre1 P., Stephens1 G., Haberstock-Debic1 H., Jurek2 M., Gretler2 D., Phillips1 D.R.
11Biology 22Clinical, Portola Pharmaceuticals Inc., South San Francisco, CA, USA
How-to-cite Conley PB, Andre P, Stephens G, Haberstock-Debic H, Jurek M, Gretler D, Phillips DR. ADP-mediated aggregation as a pharmacodynamic assay underestimates the antithrombotic activity of elinogrel, a competitive, reversible P2Y12 inhibitor, relative to clopidogrel. Journal of Thrombosis and Haemostasis 2009; Volume 7, Supplement 2: Abstract PP-TH-027
Mass-action-based P2Y12 inhibitors are being developed to overcome the limitations of clopidogrel (an irreversible inhibitor) including its variable and inconsistent level of platelet inhibition caused in part by the dependency on hepatic metabolism. The present study was designed to identify the appropriate pharmacodynamic (PD) assay to monitor the antiplatelet activity of elinogrel, a competitive P2Y12 inhibitor. In Phase I studies in healthy subjects, elinogrel (100 mg bid) was compared in multiple PD assays to clopidogrel (75 mg qd) at steady state in presence of aspirin (325 mg qd). Using light transmittance aggregometry (LTA), we found that the ADP concentration used to initiate aggregation directly altered the levels of inhibition of elinogrel (55% (5 μM ADP) vs 33% (20 μM ADP) much more than that of clopidogrel (66% (5 μM ADP) vs 52% (20 μM ADP)). In contrast, in a perfusion chamber assay (RTTP2.0) which reproduces the arterial thrombotic reaction triggered by collagen and relies on blood-borne ADP to maintain thrombus stability, we found elinogrel to be more potent at inhibiting thrombosis than clopidogrel (83 vs. 75%) despite lower levels of inhibition in LTA. These observations likely reflect differences in mechanism of action and are attributed to the use of supra-physiological concentrations of ADP (e.g., 5–20 μM ADP) in LTA. In agreement with modeling studies that established the ADP concentration released from a growing thrombus to be < 1 μM, we found that 300 nM ADP was sufficient to stabilize thrombi under arterial shear conditions in the RTTP2.0 assay. These data indicate that exogenously added ADP competes with elinogrel for binding to the receptor, thus underestimating the true antithrombotic activity of this class of inhibitor, relative to an irreversible inhibitor (thienopyridine), whereas a thrombosis assay reflects the concentration of P2Y12 inhibitor required to inhibit the concentrations of ADP necessary to stabilize thrombi.
Disclosure of interest: All authors are employees and shareholders in Portola Pharmaceuticals.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
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