Bioequivalence of two tablet formulations of clopidogrel in healthy argentinian volunteers: A single-dose, randomized-sequence, open-label crossover study

• Published in: Clinical therapeutics 2010, Vol.32 (1), p.161-170
• Main Authors: Di Girolamo, Guillermo, MD, PhD, Czerniuk, Paola, MD, Bertuola, Roberto, PhD, Keller, Guillermo A., MD
• Format: Article
• Language: English
• Subjects: Acute coronary syndromes; Adenosine; Administration, Oral; Adult; Angina pectoris; Angioplasty; Area Under Curve; Argentina; Aspirin; Bioavailability; Bioequivalence; Biological and medical sciences; Cardiology; Chromatography, High Pressure Liquid; clopidogrel; Cross-Over Studies; Cytochrome; Drug dosages; Drugs, Generic - administration & dosage; Drugs, Generic - pharmacokinetics; Female; Humans; Internal Medicine; Male; Medical Education; Medical sciences; Metabolism; Metabolites; Pharmacodynamics; Pharmacokinetics; Pharmacology. Drug treatments; Plasma; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - blood; Platelet Aggregation Inhibitors - pharmacokinetics; Reference Values; Scientific imaging; Tablets; Tandem Mass Spectrometry; Task forces; Therapeutic Equivalency; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - blood; Ticlopidine - pharmacokinetics; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2010.01.010

Abstract Background: Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Thienopyridines, particularly clopidogrel, are highly effective in reducing in-stent thrombosis and functional inhibition of adenosine diphosphate-induced platelet activation. Objective: The aim of this study was to evaluate the bioequivalence of a new generic formulation of clopidogrel 75-mg tablets (test) and the available branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. Methods: This was a randomized-sequence, openlabel, 2-period crossover study conducted in healthy white volunteers in the fasted state. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. Clopidogrel concentrations were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test:reference) for Cmax and AUC0-last were within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports. Results: Twenty-four volunteers (13 male, 11 female; mean [SD] age, 33.7 [5.2] years [range, 21–42 years]; weight, 72.4 [6.83] kg [range, 59–82 kg]) were enrolled in and completed the study. The geometric mean Cmax for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC0-t was 1911.53 and 2053.09 pg · h/mL, and the geometric mean AUC0-∞ ) was 2021.33 and 2188.25 pg · h/mL. The geometric mean ratios (test:reference) for Cmax , AUC0-t , and AUC0-∞ ) were 96.09% (90% CI, 90.71–101.78), 93.10% (90% CI, 85.57–101.3), and 92.37% (90% CI, 85.06–100.31), respectively. There were no significant differences in pharmacokinetic parameters between groups. No adverse events were reported. Conclusion: In this single-dose study in healthy fasted volunteers, the test formulation of clopidogrel tablets met the US and Argentinian regulatory criterion for bioequivalence to the reference formulation.