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Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers.

AbstractAIMS:
This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44-3888.
METHODS:
The study consisted of three parts. Part I was an open ascending-dose study to determine target effect ranges of sibrafiban. Part II, a double-blind, placebo-controlled, parallel-group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double-blind, placebo-controlled, ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban.
RESULTS:
At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were non-linear because of the saturable binding to the glycoprotein IIb-IIIa receptor. Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml-1. At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation was about 20-30%. At the higher doses, ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation (prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre-set level of acceptance.
CONCLUSIONS:
With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44-3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.
AuthorsB Wittke, I J Mackie, S J Machin, U Timm, M Zell, T Goggin
JournalBritish journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 47 Issue 5 Pg. 521-30 (May 1999) ISSN: 0306-5251 [Print] England
PMID10336576 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article)
Chemical References
  • Amidines
  • Heterocyclic Compounds
  • Oximes
  • Peptide Fragments
  • Piperidines
  • Platelet Aggregation Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Prodrugs
  • Receptors, Thrombin
  • Ro 44-3888
  • Ro 48-3656
  • Adenosine Diphosphate
  • sibrafiban
Topics
  • Adenosine Diphosphate (pharmacology)
  • Administration, Oral
  • Adult
  • Amidines (blood, urine)
  • Area Under Curve
  • Contusions (chemically induced)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Heterocyclic Compounds (blood)
  • Humans
  • Male
  • Oximes (adverse effects, blood, pharmacokinetics)
  • Peptide Fragments (pharmacology)
  • Piperidines (adverse effects, blood, pharmacokinetics, urine)
  • Platelet Aggregation (drug effects)
  • Platelet Aggregation Inhibitors (adverse effects, pharmacokinetics)
  • Platelet Glycoprotein GPIIb-IIIa Complex (antagonists & inhibitors, metabolism)
  • Prodrugs (adverse effects, pharmacokinetics)
  • Receptors, Thrombin (chemistry)

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