Bioequivalence and tolerability study of two brands of clopidogrel tablets, using inhibition of platelet aggregation and pharmacodynamic measures.

Background: The role of platelets in acute cardiovascular atherothrombotic events has been well established and attention has focused on platelet inhibition therapy. Clopidogrel is a novel thienopyridine inhibitor of adenosine diphosphate-induced platelet activation. Recent studies have shown that in the setting of coronary angioplasty/stenting, a loading dose of 300 mg followed by 75 mg once daily is required for optimum benefit.

Objective: This study assessed the bioequivalence and tolerability of 2 oral formulations of clopidogrel 75-mg tablets.

Methods: This 10-day, open-label, randomized, parallel-group, comparative bioequivalence and tolerability study was carried out in the Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (Hyderabad, India). Young healthy male volunteers were enrolled. Subjects were randomized to receive one of two 75-mg tablet formulations of clopidogrel (Clopivas(®) [test formulation] or Plavix(®) [reference formulation]). Subjects first received a 300-mg loading dose (four 75-mg tablets) on day 1, followed by 75 mg (1 tablet) at 8:00 AM daily for the next 6 days. Inhibition of platelet aggregation, which is the pharmacologic basis for the therapeutic efficacy of antiplatelet agents, and the effect on bleeding time were used as the pharmacodynamic assessment criteria. Pharmacodynamic variables included mean of maximum activity of percentage of inhibition of platelet aggregation (Emax), mean time to reach Emax (tmax), and mean area under the activity-time curve from time 0 to 168 hours (AUC0-168). Tolerability assessments included blood pressure and heart rate measurements before and at regular intervals (every hour for 12 hours and then at 24 hours) over a 24-hour period after drug administration. Clinical tolerability was assessed using adverse effects, platelet count (assessed on days 3, 6, and 10 after first-dose administration), and neutrophil count (assessed on day 10 after first-dose administration).

Results: Twenty subjects were enrolled (mean [SD] age, 26.5 [2.9] years [range, 22-32 years]). Emax, tmax, and AUC0-168 were similar between the 2 groups, as was bleeding time. The 90% CIs were within the bioequivalence acceptance range of 80% to 125%. One subject (10%) in the Plavix group experienced mild headache; no serious adverse effects were reported, and none of the subjects dropped out due to an adverse effect. Platelet and neutrophil counts were found to be within normal limits.

Conclusions: In this study of healthy male volunteers, the 2 tablet preparations of clopidogrel showed bioequivalence. However, the sample size was smaller than that generally recommended for a bioequivalence study, and additional studies with larger sample sizes are needed.