PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES FOLLOWING SINGLE AND MULTIPLE DOSES OF ROLAFAGREL, A NOVEL INHIBITOR OF THROMBOXANE SYNTHASE, IN NORMAL VOLUNTEERS

The pharmacokinetics and pharmacodynamics of rolafagrel (FCE 22178), a novel thromboxane synthase inhibitor, were evaluated after single and multiple oral doses in eight healthy volunteers. After a single dose (400 mg), the drug was absorbed rapidly, peak plasma concentrations be ing attained within 2 h in all subjects. Elimination followed a biphas ic course, with a rapid initial decline followed after 12-24 h by a la te phase with a terminal half-life of about 10 h. About 100% of the ad ministered dose could be recovered in urine within 72 h, mostly in con jugated form. During multiple dosing (400 mg t. i. d. for 5 days), ste ady-state conditions were approached on day 2 and AUC values over a do sing interval were similar to those observed after a single dose (72.3 vs 76.3 mu g.ml(-1).h). Pharmacokinetic parameters calculated after m ultiple doses were similar to those observed after a single dose (C-ma x: 20.1 vs 18.2 mu g.ml(-1); t(max): 1.2 vs 1.1 h; terminal half-life: 10.9 vs 11.4 h; CL: 85.2 vs 70.4 ml.h(-1).kg(-1); V: 1.23 vs 1.241.kg (-1)). Platelet generation of thromboxane B-2, the stable breakdown pr oduct of thromboxane A(2), was inhibited by 85% at a plasma rolafagrel concentration of about 4 mu g.ml(-1), and only a small increase in in hibition was observed at higher concentrations.