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. 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 %5 mg Fradafiban continuously infused over 30 minutes reversibly inhibited platelet aggregation in platelet-rich plasma ex vivo in response to 20 mu/mol/L. ADP (5 mg, 100% inhibition at 27 minutes after administration) and to both 1.0 (5 mg, 100%) and 10 mu g/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 greater than or equal to 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 or 1 week without signs of loss of the antiplatelet activity.