Aims Fibrinogen receptor antagonists show a close relationship between plas
ma concentrations and inhibitory effect. Optimal efficacy at an acceptable
bleeding risk requires low inter- and intrasubject variability on low peak
trough fluctuation in receptor occupancy and therefore also of plasma conce
ntrations. Therefore, the enteral absorption of lefradafiban, an orally ava
ilable fibrinogen receptor antagonist prodrug, was investigated after local
administrations to different sites of the gastrointestinal tract in order
to investigate the feasibility of an oral extended release formulation.
Methods Twelve healthy male subjects received in a randomised, open-labelle
d, four-period crossover trial four consecutive administrations of lefradaf
iban: 1. orally; 2. administration into the jejunum, 3. administration into
the lower jejunum/ileum (300 cm distally to the teeth), and 4. administrat
ion into the lumen of the sigmoid region (30 cm proximally to the anus). Lo
cal intestinal administrations were performed through a gastrointestinal tu
be.
Results Compared with oral administration, ratios [mean (two-sided 90% conf
idence intervals)] of maximum drug plasma concentrations and AUC(0,24 h) of
fradafiban were 1.05 (0.80,1.39) and 1.06 (0.85,1.31) after jejunal, 0.98
(0.75,1.30) and 0.98 (0.79,1.21) after ileal, 0.52 (0.39,0.69) and 0.68 (0.
55,0.85) after colonic administration. Urinary excretion of fradafiban was
about 16% of the dose after oral, jejunal and ileal applications whereas af
ter rectal administration about 11% were excreted.
Conclusions Lefradafiban is absorbed throughout the entire gastrointestinal
tract. Therefore, an extended release formulation seems to be feasible wit
h regard to bioavailability.