(Circulation. 1997;96:1130-1138.)
© 1997 American Heart Association, Inc.
Articles |
Profound and Sustained Inhibition of Platelet Aggregation by Fradafiban, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, and Its Orally Active Prodrug, Lefradafiban, in Men
From the Departments of Biological Research (T.H.M., H.W.), Pharmacokinetics and Metabolism (R.B.), Chemistry (F.H.), and Project Management (J.K.) and the Center of Clinical Pharmacology (H.N.), Dr Karl Thomae GmbH, Biberach, Germany.
Correspondence to Dr Thomas H. Müller, Blood Transfusion Center, German Red Cross, Brandenburger Str. 21, D-26133 Oldenburg, Germany. E-mail ckmthm{at}nord.de
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 µmol/L ADP (5 mg, 100% inhibition at 27 minutes
after administration) and to both 1.0 (5 mg, 100%) and 10 µg/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
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.
Key Words: platelet aggregation inhibitors • trials • pharmacology • glycoproteins • platelets
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