Using thrombelastography to determine the efficacy of the platelet glycoprotein IIb/IIIa antagonist, roxifiban, on platelet/fibrin-mediated clot dynamics in humans.
The effect of platelet glycoprotein IIb/IIIa antagonists on the dynamics of platelet/fibrin clot formation and strength was determined using thrombelastography (TEG) under conditions of recalcification or tissue factor addition. In the present investigation, the effect of roxifiban (class I) on ex vivo clot dynamics using recalcified blood was tested in normal, healthy volunteers (n = 7) dosed with 1 mg BID roxifiban for 9 days. Roxifiban inhibited platelet aggregation induced by 20 mumol/l adenosine diphosphate by 60-90% but did not significantly affect any of the TEG parameters either at peak, trough, or subtrough drug levels. Addition of 30 nmol/l roxifiban free acid (XV459; which is ineffective by itself to modify TEG parameters) to human blood obtained from roxifiban-treated subjects resulted in 45-60% (P < 0.01) inhibition of clot strength (maximum amplitude), 90-100% (P < 0.01) inhibition of initial kinetic of clot development (angle alpha), and 50-70% (P < 0.01) inhibition of early clot initiation (K). These data suggest that a subthreshold blood level of 40-50 nmol/l roxifiban active form was achieved in those subjects, as estimated from an in vitro calibration with XV459. These data indicate (not studied) that roxifiban, at a targeted clinical dosing regimen, failed to achieve sufficient exposure to modulate platelet-mediated clot retraction.
Mousa
Shaker A
SA
Pharmaceutical Research Institute and Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208-3492, USA. mousas@acp.edu
Bozarth
Jeffrey M
JM
Seiffert
Dietmar
D
Feuerstein
Giora Z
GZ
D000578:Amidines / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D002122:Calcium Chloride / Q000494:pharmacology; D018592:Cross-Over Studies; D005337:Fibrin / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D012016:Reference Values; D013916:Thrombelastography / Q000295:instrumentation / Q000379:methods*
D000578:Amidines; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005337:Fibrin; D002122:Calcium Chloride; C118235:roxifiban; D001241:Aspirin