Bioequivalence Study of Two Different Clopidogrel Bisulfate Film-coated Tablets

Abstract

Objective:

The aim of the present study was to evaluate the bioequivalence of two oral clopidogrel (CAS 113665-84-2) formulations.

Method:

The study was conducted as a monocentric, open, randomized, single-dose, two-period crossover trial in 48 healthy volunteers with a duration of hospitalization of approximately 24 h after dosing on day 1 and with a real wash-out period of 7 days.

Blood samples were collected for 24 h post dosing in each period. The plasma was separated and the concentrations of clopidogrel were determined by a LC-MS/MS method. AUC_0–tlast, C_max, t _max, AUC_0–inf, MRT and t _1/2 were calculated for both formulations.

Results:

The arithmetic means of AUC_0–tlast and C _max were 3656.01 pg · h/ml and 1970.22 pg/ml for the test formulation and 3771.51 pg · h/ml and 1756.52 pg/ml, respectively, for the reference formulation. The mean t _max was 1.16 h for the test and 1.13 h for the reference formulation. The point estimators of the ratios of the test and reference formulations for AUC_0–tlast and C _max were 1.042 and 1.115, respectively. Furthermore, the 90% confidence intervals calculated by means of ANOVA-log for the first primary endpoint of the trial, the intra-individual ratio (T/R) of AUC_0–tlast of clopidogrel was between 0.932 and 1.165. The 90% confidence interval calculated by means of ANOVA-log for C _max of clopidogrel was between 0.973 and 1.277. The 90% confidence intervals for both parameters were within the predefined acceptance ranges (0.80–1.25 for AUC_0–tlast and 0.75–1.33 for C _max ). The intraindividual coefficients of variation determined by means of ANOVA-log were 33.51% for AUC_0–tlast and 41.29% for C_max.

Conclusion:

While both products were bioequivalent in terms of the rate and extent of absorption, the present study also confirmed a high variability for Clopidogrel suggesting high volunteer numbers in bioequivalence trials.

Key words

CAS 113665-84-2 - clopidogrel, bioequivalence, clinical pharmacokinetics, highly variable drug, replicate trial design - Platelet aggregation inhibitors

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