Preliminary assessment of a novel thromboxane A2 receptor-blocking drug, GR32191, in healthy subjects

Abstract

The effects of GR32191, a novel, specific, thromboxane A2 receptor-blocking drug, on platelet aggregation induced by U-46619 and adenosine diphosphate (ADP) ex vivo, have been examined in healthy male subjects. In two placebo-controlled studies (the first, a single-dose, crossover study, and the second, a group comparative, multiple-dose study), concentration-effect curves for both agonists were constructed in whole blood by counting platelets electronically before and after dosing. Single oral doses of 0.125 and 0.25 mg/kg (four subjects) and 0.5 and 1.0 mg/kg (four subjects) produced dose-related shifts to the right in U-46619 concentration-effect curves. The elimination half-life of GR32191 (up to 8 hours postdrug) was approximately 2 hours. Multiple dosing with GR32191, 17.5 mg (equivalent to 0.25 mg/kg for a 70 kg subject), three times daily (three subjects) or every 12 hours (six subjects), resulted in a cumulative inhibitory effect on U-46619 platelet aggregation in the apparent absence of a build-up of plasma concentrations of GR32191. Primary platelet aggregation induced by ADP was unaffected by GR32191. Multiple dosing had no effect on lancet bleeding time, and no drug-related changes were seen in routine laboratory hematologic and biochemical screens. GR32191 was well tolerated, although a subject with a history of drug-induced rectal bleeding reported the same symptom while taking GR32191.