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Profound and sustained inhibition of platelet aggregation by Fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, Lefradafiban, in men.

Abstract：

BACKGROUND:Clinical trials have demonstrated that platelet glycoprotein (GP) IIb/IIIa antagonists effectively prevent acute thrombotic events. Orally active GP IIb/IIIa antagonists are essential to evaluate the clinical benefit of long-term treatment. We therefore investigated platelet inhibition by the GP IIb/IIIa antagonist Fradafiban (BIBU 52; Fradafiban is the recommended INN of BIBU 52) and its orally administered prodrug, Lefradafiban (BIBU 104; Lefradafiban is the recommended INN of BIBU 104) in healthy subjects. METHODS AND RESULTS:The activity and plasma levels of Fradafiban and Lefradafiban were evaluated in double-blind, placebo-controlled studies in 130 healthy male subjects. One to 15 mg Fradafiban continuously infused over 30 minutes reversibly inhibited platelet aggregation in platelet-rich plasma ex vivo in response to 20 micromol/L ADP (5 mg, 100% inhibition at 27 minutes after administration) and to both 1.0 (5 mg, 100%) and 10 microg/mL (15 mg, 97+/-3%) collagen. Single oral doses of Lefradafiban inhibited ADP-induced aggregation by 59+/-14% (50 mg [mean+/-SD]; n=8), 90+/-12% (100 mg), and 99+/-2% (150 mg) 8 hours after administration. Correlations between activity and Fradafiban plasma levels were identical after Fradafiban and Lefradafiban treatment. After day 1, oral TID Lefradafiban treatment for 7 days inhibited aggregation by > or = 31+/-9.6% (25 mg TID; n=8), 53+/-12% (50 mg; n=7), and 88+/-6.6% (75 mg; n=8) just before the next dose. A similar correlation between the activity and Fradafiban plasma levels was observed at days 1, 2, and 7. CONCLUSIONS:Oral administration of Lefradafiban maintains the potent platelet GP IIb/IIIa antagonism of Fradafiban during treatment of healthy subjects for 1 week without signs of loss of the antiplatelet activity.

journal_name

Circulation

journal_title

Circulation

authors

Müller TH,Weisenberger H,Brickl R,Narjes H,Himmelsbach F,Krause J

doi

10.1161/01.cir.96.4.1130

subject

Has Abstract

pub_date

1997-08-19 00:00:00

pages

1130-8

issue

eissn

0009-7322

issn

1524-4539

journal_volume

pub_type

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Profound and sustained inhibition of platelet aggregation by Fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, Lefradafiban, in men.