The effect of repeated doses of clopidogrel, a novel platelet ADP-receptor antagonist, on platelet aggregation and its tolerance were assessed in two randomized, double-blind studies in healthy male adults. In each of the four successive dose groups in Study I, 6 subjects received either clopidogrel 25, 50, 100, or 150 mg once daily and 2 received placebo for 16 days, according to a rising dose design. In each of the three successive treatment groups of Study II, 9 subjects received clopidogrel (50, 75, or 100 mg once daily) in the morning, 3 received triclopidine 250 mg twice daily and 3 received placebo for 14 days. In both studies, the inhibition of platelet aggregation induced by 5 microM of ADP was measured before dosing (baseline), then at regular intervals during and after treatment. Bleeding time was generally assessed at the same time points as platelet aggregation. In both studies, the inhibition of platelet aggregation reached steady state after day 6 dosing. Mean steady-state percent inhibition of platelet aggregation was 30%, 46%, 53%, and 73% for clopidogrel 25, 50, 100, and 150 mg, respectively, in Study I; and 54%, 52%, 47%, and 43% for clopidogrel 50, 75, 100 mg, and for ticlopidine, respectively, in Study II. After treatment discontinuation, statistically significant inhibition of platelet aggregation persisted for up to 8 days. In Study I, up to 75 mg repeated doses, mean bleeding time prolongation factor did not exceed 2, but increased further to 3.5 and 5.5 at a clopidogrel dose of 100 mg and 150 mg, respectively. In study II, prolongation factors during treatment did not exceed 2.2 for clopidogrel (in the 75 mg dose group) and 1.6 for ticlopidine 500 mg. Recovery of bleeding time was observed within 7-8 days. Treatments were well tolerated, and no serious clinical events or important changes in laboratory parameters were recorded. These data were consistent with those obtained in atherosclerotic patients and showed that the plateau response for the inhibition of platelet aggregation was reached at the 75 mg dose, for which bleeding time prolongation was approximately 2.