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


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.
Müller
T H
TH
Department of Biological Research, Dr Karl Thomae GmbH, Biberach, Germany. ckmthm@nord.de
Weisenberger
H
H
Brickl
R
R
Narjes
H
H
Himmelsbach
F
F
Krause
J
J
D000284:Administration, Oral; D000328:Adult; D001713:Biphenyl Compounds / Q000097:blood / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology*
D001713:Biphenyl Compounds; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D011759:Pyrrolidines; C107918:lefradafiban; C107917:fradafiban