Bioequivalence Study of Clopidogrel Bisulfate Film-coated Tablets

Abstract

The aim of the present study was to evaluate the bioequivalence of two clopidogrel (CAS 120202-66-6) formulations. The study was performed according to an open, cross-over design in one study center in 36 healthy male and female volunteers, comparing a new generic product (tablets containing clopidogrel bisulfate, 75 mg) with the originator product (reference). In each of the two study periods (separated by a wash-out of 7 days) a single dose of 150 mg (test or reference) was administered. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of clopidogrel were determined by an LC/MS/MS method. AUC0-inf, AUC0-t, Cmax, Tmax and T(1/2 el) were calculated for both formulations. The mean AUC0-inf, AUC0-t and Cmax were 29.94 ng x h/mL, 29.53 ng x h/mL and 7.386 ng/mL, respectively, for the test formulation and 29.24 ng x h/mL, 28.83 ng x h/mL and 7.921 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1.25 h. The point estimators of the ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 101.17%, 101.13% and 90.96%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf and AUC0-t were narrow and symmetrical around 100%, i.e. from 96.38% to 106.21% for AUC0-inf and from 96.20% to 106.30% for AUC0-t, whereas the confidence interval for Cmax was 84.07% to 98.41%. In can be concluded that the two clopidogrel formulations (test formulation of clopidogrel bisulfate and reference formulation) are bioequivalent in terms of the rate and extent of absorption.

Development and validation of an HPLC–MS/MS method to determine clopidogrel in human plasma. Use of incurred samples to test back-conversion

“…Keeping this in mind, and dividing by two the pharmacokinetic data from the studies with a twofold higher dose, the results of the first study in the table [4] are very similar to those obtained with the first method here presented, which was inadequate to control back conversion. The results of the other published studies [5,6] are very close to the results gathered with Methods 2 and 3 in conditions controlling back conversion.…”

“…Product ion spectra of clopidogrel and d3-clopidogrel were similar to those reported [4]. The molecular ion corresponding to 35 Cl (322.2) was chosen as precursor ion for clopidogrel in the MRM method used for quantification, while for d3-clopidogrel the isotope 37 Cl was preferred, despite being less intense, in order to obtain optimal analytical selectivity.…”

“…The analytical range to be validated was chosen on the basis of the expected plasma concentrations [4]. Spiked plasma samples were prepared for calibration curves (8 points) and quality controls (4 different concentration levels) as previously detailed in Section 2.3.…”

“…Recently, LC-MS/MS methods with adequate sensitivity to quantify clopidogrel in biological fluids have been developed [4][5][6]. The main application of such methods was the development of generic formulations of clopidogrel according to bioequivalence regulations (EMEA, FDA, etc.…”

Sensitivity enhancement and matrix effect evaluation during summation of multiple transition pairs—case studies of clopidogrel and ramiprilat

“…Several methods are available for the determination of clopidogrel (Shin and Yoo, 2007;Nirogi et al, 2006;Lainesse et al, 2004) and ramiprilat (Zhu et al, 2002) using tandem mass spectrometry. Both compounds produce stable and intense multiple MRM transition pairs as evidenced by the positive ion mass spectral data and therefore are amenable for the proposed summation approach of multiple MRM transition pairs to improve sensitivity.…”