Pharmacokinetics and the antiplatelet effect of a new clopidogrel formulation, clopidogrel besylate, in healthy subjects

Abstract

Background: Clopidogrel, a thienopyridine derivative, is an inhibitor of platelet aggregation induced by adenosine diphosphate (ADP). We compared the pharmacokinetics and the antiplatelet effect of two clopidogrel formulations (clopidogrel besylate (test) and clopidogrel bisulfate (reference)). Subjects and methods: The study was conducted in 40 healthy subjects in a randomized, open-label, 2-period crossover manner. Each subject received a single loading dose of 150 mg clopidogrel on Day I followed by a daily dose of 75 mg clopidogrel from Day 2 to Day 7. After the first dose blood samples for pharmacokinetic analysis of clopidogrel and SR26334 were collected over 24 h. The pharmacodynamic variables, i.e., the inhibition of ADP-induced platelet aggregation, were measured over 264 h. Results: No serious adverse events occurred during the study period. The mean plasma concentration-time profiles of clopidogrel and SR26334 for the two formulations were comparable. The 90% confidence intervals (CIs) for the log-transformed ratios for pharmacokinetic parameters (C(max) and AUC) of SR26334 fell within the predefined pharmacokinetic equivalence range of 80 - 125%. However, the upper limits of 90% CI of C(max) and AUC for clopidogrel exceeded the equivalence range. The two formulations showed similar antiplatelet profiles. The 90% CIs of Delta E(max) and Delta AUEC of platelet aggregation inhibition fell within the equivalence range of 80 125%. Conclusion: Both clopidogrel formulations were well-tolerated. The study population showed no serious AEs. The test formulation proved pharmacokinetically non-inferior to the reference formulation. The test formulation showed an antiplatelet effect on ADP-induced platelet aggregation similar to the reference formulation. The two formulations were considered pharmacodynamically equivalent in terms of platelet aggregation inhibition.