Beraprost sodium-fluindione combination in healthy subjects: pharmacokinetic and pharmacodynamic aspects

Beraprost sodium (BPS), an orally active PGI2 (prostaglandine I2) analogue possesses vasodilatating and platelet aggregation inhibiting properties. It is being developed in peripheral arterial occlusive disease. As in future clinical practice BPS might be co-prescribed with oral anticoagulants, we i nvestigated its interaction with fluindione, a vitamin K antagonist in heal thy subjects in a randomised, double-blind, placebo-controlled, crossover s tudy. Twelve healthy Caucasian male subjects randomly received BPS 40 mu g t.i.d, or placebo for 3 days. There was a 7 day wash out between the two tr eatment periods. On day 3 of each treatment, the subjects ingested concomit antly a single oral dose of 20 mg of fluindione. The main assessment criter ion was fluindione's pharmacokinetics. Secondarily, pharmacodynamic measure ments of coagulation (prothrombin time, and International Normalised Ratio, INR) and platelet function (in vitro closure time assessed by PFA-100(TM)) were performed. Fluindione was assayed by HPLC with UV detection up to 96 h post-drug. No statistical difference could be evidenced on any fluindione pharmacokinetic parameters between BPS and placebo phases: t(1/2) (h): 35. 9 (8.2) vs. 34.0 (4.2) [90% CI 105.8 (95.5-116.2)]; T-max (h): 2.0 (0.5-6.0 ) vs. 4.0 (0.5-6.0) [90% CI 136.4 (70.7-208.9)]; C-max (mg/L): 3.1 (0.6) vs . 2.9 (0.5) [90% cr 94.1 (85.8-103.2)]; AUC 9-inf (mg/h/L): 117.0 (31.5) vs . 113.9 (33.8) [90% CI 97.6 (87.5-108.8)]. The studied doses of BPS did not affect platelet function, at least as assessed by the in vitro platelet fu nction testing. Twenty milligrams of fluindione marginally modified the PT ratio and INR, however, no statistically significant difference was found b etween BPS and placebo phases. In conclusion, a 3 day regimen of BPS 40 mu g t.i.d. by oral route does not seem to affect pharmacokinetic parameters o f a fluindione 20 mg single dose. (C) 2000 Editions scientifiques et medica les Elsevier SAS.