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. AUC0–tlast, Cmax, t max, AUC0–inf, MRT and t 1/2
were calculated for both formulations.
Results:
The arithmetic means of AUC0–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 AUC0–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 AUC0–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 AUC0–tlast and 0.75–1.33 for C max ). The intraindividual coefficients of variation determined by means of ANOVA-log
were 33.51% for AUC0–tlast and 41.29% for Cmax.
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
