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 being attained within 2 h in all subjects. Elimination followed a biphasic course, with a rapid initial decline followed after 12-24 h by a late phase with a terminal half-life of about 10 h. About 100% of the administered dose could be recovered in urine within 72 h, mostly in conjugated form. During multiple dosing (400 mg t.i.d. for 5 days), steady-state conditions were approached on day 2 and AUC values over a dosing interval were similar to those observed after a single dose (72.3 vs 76.3 micrograms.ml-1.h). Pharmacokinetic parameters calculated after multiple doses were similar to those observed after a single dose (Cmax: 20.1 vs 18.2 micrograms.ml-1; tmax: 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 1.24 l.kg-1). Platelet generation of thromboxane B2, the stable breakdown product of thromboxane A2, was inhibited by 85% at a plasma rolafagrel concentration of about 4 micrograms.ml-1, and only a small increase in inhibition was observed at higher concentrations.