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Bioequivalence of two tablet formulations of clopidogrel in healthy Argentinian volunteers: a single-dose,
Guillermo Di Girolamo1, Paola Czerniuk, Roberto Bertuola
1Unidad de Farmacocinética Clínica, Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. gdigirolamo@fmed.uba.ar
Insights
A new generic clopidogrel tablet formulation demonstrated bioequivalence to the branded version in healthy volunteers. This finding supports its regulatory approval for marketing, offering a potentially more accessible treatment option for patients.
Area of Science:
- Pharmacology and Therapeutics
- Clinical Pharmacy
- Bioequivalence Studies
Background:
- Platelet activation is central to coronary thrombosis and myocardial infarction.
- Thienopyridines, like clopidogrel, effectively inhibit platelet aggregation.
- Clopidogrel is crucial in preventing stent thrombosis and managing cardiovascular events.
Purpose of the Study:
- To assess the bioequivalence of a new generic clopidogrel 75-mg tablet formulation against the reference branded product.
- To meet regulatory requirements for the marketing of the generic clopidogrel formulation in Argentina.
Main Methods:
- A randomized, open-label, 2-period crossover study in healthy volunteers.
- Single oral dose administration of test and reference clopidogrel formulations with a 7-day washout period.
- Pharmacokinetic analysis of clopidogrel concentrations using LC-MS/MS, with bioequivalence defined by 90% CIs for Cmax and AUC(0-last) between 80% and 125%.
Main Results:
- Twenty-four healthy volunteers completed the study.
- Geometric mean ratios (test:reference) for Cmax, AUC(0-t), and AUC(0-infinity) were 96.09%, 93.10%, and 92.37%, respectively.
- All pharmacokinetic parameters fell within the bioequivalence criteria, with no reported adverse events.
Conclusions:
- The generic clopidogrel 75-mg tablet formulation is bioequivalent to the reference formulation.
- The study met US and Argentinian regulatory standards for bioequivalence.
- This supports the market entry of the generic clopidogrel formulation.
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, open-label, 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 C(max) and AUC(0-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 C(max) for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC(0-t) was 1911.53 and 2053.09 pg . h/mL, and the geometric mean AUC(0-infinity)) was 2021.33 and 2188.25 pg . h/mL. The geometric mean ratios (test:reference) for C(max), AUC(0-t), and AUC(0-infinity)) 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.
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