Pharmacokinetics and pharmacodynamics of sibrafiban (Ro 48-3657), an orally active IIb/IIIa antagonist, administered alone or in combination with heparin, aspirin, and recombinant tissue-type plasminogen activator in beagles.
This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of sibrafiban (Ro 48-3657) in the presence of aspirin, heparin, and recombinant tissue-type plasminogen activator (rt-PA) in beagles. Sibrafiban is a double prodrug that undergoes bioconversion to the inactive prodrug Ro 48-3656 and to the active IIb/IIIa antagonist, Ro 44-3888, after oral administration. After oral sibrafiban, peak Ro 48-3656 plasma concentrations were observed earlier than Ro 44-3888 and were five- to sixfold higher than Ro 44-3888 peak concentrations. Administration of sibrafiban with heparin and aspirin or heparin and rt-PA did not alter sibrafiban PK. Ro 48-3656 and Ro 44-3888 PK and inhibition of platelet-aggregation profiles in groups treated with sibrafiban and heparin/aspirin or sibrafiban and heparin/rt-PA were similar to those of the group receiving sibrafiban alone. Sibrafiban resulted in >80% inhibition of adenosine diphosphate (ADP)-mediated platelet aggregation and an approximate sixfold increase in bleeding time (BT) compared with baseline measurements. The BT increase was greater in the sibrafiban, heparin, and rt-PA-treated group, during rt-PA administration, compared with the group treated with sibrafiban alone. The recovery of platelet aggregation may be slower after administration of sibrafiban with heparin and rt-PA. Sibrafiban had no effect on rt-PA PK or heparin PD.
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Department of Pharmacokinetics and Metabolism, Genentech, Inc., South San Francisco, California, USA.
Lin
Y S
YS
Reynolds
T
T
Shaheen
A
A
Christian
B J
BJ
D000284:Administration, Oral; D000578:Amidines / Q000493:pharmacokinetics; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001760:Bleeding Time; D004285:Dogs; D006493:Heparin / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics; D008297:Male; D010091:Oximes / Q000493:pharmacokinetics* / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D000578:Amidines; D006571:Heterocyclic Compounds; D010091:Oximes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; C100916:Ro 44-3888; C110992:Ro 48-3656; D006493:Heparin; D010959:Tissue Plasminogen Activator; D001241:Aspirin; C100917:sibrafiban