title: Pharmacokinetics and pharmacodynamics of Ro 44-3888 after single ascending oral doses of sibrafiban, an oral platelet aggregation inhibitor, in healthy male volunteers.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 CH-Basel.
authors.forename: B
authors.initials: B
authors.lastname: Wittke
authors.forename: I J
authors.initials: IJ
authors.lastname: Mackie
authors.forename: S J
authors.initials: SJ
authors.lastname: Machin
authors.forename: U
authors.initials: U
authors.lastname: Timm
authors.forename: M
authors.initials: M
authors.lastname: Zell
authors.forename: T
authors.initials: T
authors.lastname: Goggin
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000328:Adult; D000578:Amidines / Q000097:blood* / Q000652:urine; D019540:Area Under Curve; D003288:Contusions / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006571:Heterocyclic Compounds / Q000097:blood; D006801:Humans; D008297:Male; D010091:Oximes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics* / Q000652:urine; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics*; D018179:Receptors, Thrombin / Q000737:chemistry
chemical_list: D000578:Amidines; D006571:Heterocyclic Compounds; D010091:Oximes; D010446:Peptide Fragments; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D018179:Receptors, Thrombin; C100916:Ro 44-3888; C110992:Ro 48-3656; D000244:Adenosine Diphosphate; C100917:sibrafiban