Clopidogrel, a potent novel platelet ADP-receptor antagonist, induces a significant inhibition of ADP-induced platelet aggregation. Maximum inhibition of 40 to 50% is observed 2 to 5 hours after a single 400 mg dose. The same level of inhibition is achieved with 75 mg once daily at steady state, i.e., after 3 to 7 days of repeated dosing. Based on these data, two studies were undertaken to investigate whether a treatment regimen comprising a large initial dose (loading dose) of clopidogrel, followed by daily doses of 75 mg, might provide a sustained steady-state level of inhibition of platelet aggregation induced by 5 microM of ADP within hours after first dosing. In one study, 10 healthy male subjects received a 375 mg loading dose of clopidogrel on day 1, then daily doses of 75 mg from day 2 to day 10. Mean inhibition of platelet aggregation, already significant at 30 minutes, reached 55+/-8.2% (+/-SEM) at 60 minutes, and a maximum of 80+/-3.6% at 5 hours. No further significant change was observed between 5 hours and 24 hours, and from day 2 through day 10 with subsequent daily doses of 75 mg. In the second study, conducted according to a randomized, single-blind design, four parallel treatment groups of nine healthy male subjects received a loading dose of 75 mg, 150 mg, 225 mg, or 300 mg of clopidogrel on day 1, respectively, and 75 mg once daily from day 2 to day 5. Mean (+/-SD) inhibition of platelet aggregation over the 2 to 24 hours post-loading dose period was 22+/-14.5%, 21+/-13.4%, 35+/-20.6% and 31+/-13.3%, respectively. On day 5, it was 48+/-14.7%, 33 +/-14.1%, 51+/-15.7% and 40+/-10.9% for the 75, 150, 225 and 300 mg loading dose groups, respectively. The smallest day 1 to day 5 difference was observed for the 300 mg group and the largest for the 75 mg group, indicating that the development of the full inhibitory effect of clopidogrel was faster with the loading doses higher than with 75 mg, and fastest with the 300 mg loading dose. These data and those of previous studies indicate that a dose of 300 to 400 mg produces a rapid onset of the pharmacodynamic action of clopidogrel, with levels of inhibition close to steady-state reached within 2 hours.