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

J Cardiovasc Pharmacol. 1998 Sep;32(3):397-405. doi: 10.1097/00005344-199809000-00010.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Amidines / pharmacokinetics
  • Animals
  • Aspirin / pharmacology*
  • Bleeding Time
  • Dogs
  • Heparin / pharmacology*
  • Heterocyclic Compounds / pharmacokinetics
  • Male
  • Oximes / pharmacokinetics*
  • Oximes / pharmacology
  • Partial Thromboplastin Time
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / pharmacokinetics*
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
  • Recombinant Proteins / pharmacology
  • Tissue Plasminogen Activator / pharmacology

Substances

  • Amidines
  • Heterocyclic Compounds
  • Oximes
  • Piperidines
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Recombinant Proteins
  • Ro 44-3888
  • Ro 48-3656
  • Heparin
  • Tissue Plasminogen Activator
  • Aspirin
  • sibrafiban