Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression, fibrinogen binding, and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist.
The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.
Seiffert
Dietmar
D
Experimental Station E400/3255, Bristol-Meyers Squibb Company, Wilmington, DE 19880, USA. dietmar.seiffert@bms.com
Thomas
Beth E
BE
Bradley
Jodi D
JD
Munzer
Deborah A
DA
Tchinnes
Maureen A
MA
Kornhauser
David M
DM
Cain
Valerie A
VA
Hua
Tsuhung A
TA
Feuerstein
Giora Z
GZ
Martin
David E
DE
Stern
Andrew M
AM
D000244:Adenosine Diphosphate; D000328:Adult; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019007:P-Selectin / Q000096:biosynthesis; D015539:Platelet Activation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs; D018179:Receptors, Thrombin
D000578:Amidines; D015415:Biomarkers; D007555:Isoxazoles; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D018179:Receptors, Thrombin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; C118235:roxifiban