Bioequivalence study of two different clopidogrel bisulfate film-coated tablets.
OBJECTIVE
The aim of the present study was to evaluate the bioequivalence of two oral clopidogrel (CAS 113665-84-2) formulations.


METHODS
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), Cmax, tmax, AUC(0-inf), MRT and t1/2 were calculated for both formulations.


RESULTS
The arithmetic means of AUC(0-tlast) and Cmax were 3,656.01 pg x h/ml and 1970.22 pg/ml for the test formulation and 3771.51 pg x h/ml and 1756.52 pg/ml, respectively, for the reference formulation. The mean tmax 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 Cmax 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 Cmax 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 Cmax). The intraindividual coefficients of variation determined by means of ANOVA-log were 33.51% for AUC(0-tlast) and 41.29% for Cmax.


CONCLUSIONS
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.
Richter
Wolfram
W
Cooperative Clinical Drug Research and Development AG, Berlin, Germany. wrichter@ccdrdag.com
Erenmemisoglu
Aydin
A
Van der Meer
Mike John
MJ
Emritte
Nizam
N
Tuncay
Emine
E
Koytchev
Rossen
R
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D000077144:Clopidogrel; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility; D013057:Spectrum Analysis; D013431:Sulfates / Q000737:chemistry; D013608:Tablets, Enteric-Coated; D013810:Therapeutic Equivalency; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
D010975:Platelet Aggregation Inhibitors; D013431:Sulfates; D013608:Tablets, Enteric-Coated; D000077144:Clopidogrel; D013988:Ticlopidine