Abstract | AIMS: 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.
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Authors | B Wittke, I J Mackie, S J Machin, U Timm, M Zell, T Goggin |
Journal | British journal of clinical pharmacology
(Br J Clin Pharmacol)
Vol. 47
Issue 5
Pg. 521-30
(May 1999)
ISSN: 0306-5251 [Print] England |
PMID | 10336576
(Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article)
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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
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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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