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      Comparative fasting bioavailability of two clopidogrel formulations in healthy Mediterranean volunteers: an in vitro–in vivo correlation

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          Abstract

          Objective

          The aim of this study was to evaluate the bioequivalence of two drug products, generic clopidogrel bisulfate 75 mg film-coated tablets versus the reference Plavix ® clopidogrel bisulfate 75 mg film-coated tablets.

          Methods

          Bioequivalence of tablets was tested by comparisons against the reference brand product in accordance with the requirements of the Declaration of Helsinki, the current Good Clinical Practice Guidelines, and the International Conference on Harmonization.

          Results

          The relationship between concentration and peak area ratio was found to be linear within the range 24.500–1,836.600 pg/mL for clopidogrel. The correlation coefficient ( r) was always greater than 0.99 during the course of the validation. Statistical comparison of the main pharmacokinetic parameters showed no significant difference between test and reference. The point estimates (ratios of geometric mean) were 104.122%, 104.184%, and 109.091% for areas under the plasma concentration–time curve (AUC) AUC 0-last, AUC 0-∞, and peak plasma concentration C max, respectively. These pharmacokinetic parameter values of clopidogrel and its main metabolite lie within the bioequivalence limit (80%–125%) specified by the US Food and Drug Administration and the European Medicines Agency.

          Conclusion

          The tested drug product was bioequivalent to the reference drug under fasting conditions and had the same safety profile, which is important to achieve equivalent therapeutic effect with the reference.

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          Most cited references 19

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          Guidance for Industry Dissolution Testing for Immediate Release Solid Oral Dosage Forms

          (1997)
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            Guidance for Industry - Statistical Approaches to Establishing Bioequivalence

            (2001)
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              Clinical Pharmacokinetics of Clopidogrel and Its Metabolites in Patients with Cardiovascular Diseases

              Background and Objective Approximately 5–40 % of patients treated with clopidogrel do not display an adequate antiplatelet response. Clopidogrel resistance may be caused by insufficient drug absorption or impaired metabolic activation of the drug. The aim of this study was to evaluate the pharmacokinetics of clopidogrel and its metabolites in plasma samples from patients treated with high and low doses of clopidogrel, to obtain a possible explanation for antiplatelet resistance. Methods The study included patients receiving either a single 300 mg loading dose of clopidogrel (n = 17) or a 75 mg dose (n = 45) for at least 7 days before sample collection. The concentrations of clopidogrel and its metabolites—the inactive H3 and the pharmacologically active H4 isomers of the thiol metabolite and the inactive carboxylic acid metabolite—in plasma samples (stabilized with 2-bromo-3′-methoxyacetophenone) from three patients after 300 mg and from 41 patients after 75 mg of the drug were determined using a validated high-performance liquid chromatography method with tandem mass spectrometry. The non-stabilized samples from the remaining patients were analysed using a validated capillary electrophoresis method. The calculated concentrations were used to determine the pharmacokinetic parameters of the analytes. The pharmacodynamic response to clopidogrel treatment, expressed as adenosine diphosphate-induced platelet aggregation, was measured using a Multiplate analyser. Results The pharmacokinetic parameter values for the H3 and H4 isomers determined in the studied group of patients treated with clopidogrel 75 mg (maximum plasma concentration [C max] 5.29 ± 5.54 and 7.13 ± 6.32 ng/mL for H3 and H4, respectively; area under the plasma concentration-time curve from time zero to time t [AUC t ] 7.37 ± 6.71 and 11.30 ± 9.58 ng·h/mL for H3 and H4, respectively) were lower than those reported in healthy volunteers, according to the literature data. Platelet aggregation measured with a Multiplate analyser ranged between 37 and 747 AU·min. A significant correlation was found between the C max of the active H4 isomer and platelet aggregation (p = 0.025). Conclusion The C max of the active H4 isomer and platelet aggregation measured by the Multiplate analyser may serve as markers of the patient response to clopidogrel therapy.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                24 April 2015
                : 9
                : 2359-2365
                Affiliations
                [1 ]Department of Pharmacy, Faculty of Medicine and health sciences, An-Najah National University, Nablus, Palestine
                [2 ]Pharmaceutical Research Unit, Amman, Jordan
                [3 ]R&D Department, Middle East Pharmaceutical Industries Co Ltd, Riyadh, Saudi Arabia
                Author notes
                Correspondence: Abdel Naser Zaid, Department of Pharmaceutical Chemistry and Technology/Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, PO Box 7, Nablus, Palestine, Tel +972 9 234 5113, Fax +972 9 234 5982, Email anzaid@ 123456najah.edu
                Article
                dddt-9-2359
                10.2147/DDDT.S78658
                4422294
                25987833
                © 2015 Zaid et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                bioequivalence, film coating, stability, clopidogrel

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