Two randomized, single dose, 2-period, 2-sequence crossover studies were conducted to evaluate the comparative bioavailability of two clopidogrel formulations under fasting and fed conditions. Assessment of bioequivalence was based upon measurement of plasma concentrations of the parent drug, clopidogrel, and its major (inactive) metabolite, clopidogrel carboxylic acid, using improved methanol-free extraction. Bioequivalence of Krka’s formulation to the innovator’s formulation was demonstrated under both fasting and fed conditions on 205 volunteers. Confidence intervals for AUC0-t, AUC0-inf and Cmax of clopidogrel and its main metabolite were well within the acceptance range of 80.00 to 125.00 %. Food substantially increased the bioavailability of clopidogrel from both formulations, while no effect of food on the extent and rate of exposure to the metabolite was observed. The effect of food was comparable between the two formulations, as indicated by the same direction and rank of food impact on the bioavailability of both formulations.
1. P. Savi, C. Labouret, N. Delesque, F. Guette, J. Lupker and J. M. Herbert, P2Y12, a new platelet ADP receptor, target of clopidogrel, Biochem. Biophys. Res. Commun. 283 (2001) 379-383; DOI: 10.1006/bbrc.2001.4816.
2. CAPRIE Steering Committee, A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE), Lancet 348 (1996) 1329-1339; DOI: 10.1016/ S0140-6736(96)09457-3. Available online 10 January 2000.
3. L. Bonello, U. S. Tantry, R. Marcucci, R. Blindt, D. J. Angiolillo, R. Becker, D. L. Bhatt, M. Cattaneo, J. P. Collet, T. Cuisset, C. Gachet, G. Montalescot, L. K. Jennings, D. Kereiakes, D. Sibbing, D. Trenk, J. W. Van Werkum, F. Paganelli, M. J. Price, R. Waksman and P. A. Gurbel, Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate, J. Am. Coll. Cardiol. 56 (2010) 919-933; DOI: 10.1016/j.jacc.2010.04.047.
4. A. L. Frelinger III, D. L. Bhatt, R. D. Lee, D. J. Mulford, J. Wu , S. Nudurupati, A. Nigam, M. Lampa, J. K. Brooks, M. R. Barnard and A. D. Michelson, Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function, J. Am. Coll. Cardiol. 26 (2013) 872-879; DOI: 10.1016/j.jacc.2012.11.040.
5. P. Savi, J. M. Pereillo, M. F. Uzabiaga, J. Combalbert, C. Picard, J. P. Maffrand, M. Pascal and J. M. Herbert, Identification and biological activity of the active metabolite of clopidogrel, Thromb. Haemost. 84 (2000) 891-986.
6. T. A. Clarke and L. A. Waskell, The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin, Drug Metab. Dispos. 31 (2003) 53-59; DOI: 10.1124/ dmd.31.1.53.
7. P. Savi, J. Combalbert, C. Gaich, M. C. Rouchon, J. P. Maffrand, Y. Berger and J. M. Herbert, The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A, Thromb. Haemost. 72 (1994) 313-317.
8. H. Caplain, F. Donat, C. Gaud and J. Necciari, Pharmacokinetics of clopidogrel, Semin. Thromb. Hemost. 25 (1999) 25-28.
9. J. McEwen, G. Strauch, P. Perles, G. Pritchard, T. E. Moreland, J. Necciari and J. P. Dickinson, Clopidogrel bioavailability: absence of influence of food or antacids, Semin. Thromb. Hemost. 25 (1999) 47-50.
10. R. V. Nirogi, V. N. Kandikere and K. Mudigonda, Effect of food on bioavailability of a single oral dose of clopidogrel in healthy male subjects, Arzneimittelforsch. 56 (2006) 735-739; DOI: 10.1055/s-0031-1296783.
11. F. Hurbin, X. Boulenc, N. Daskalakis, C. Farenc, T. Taylor, D. Bonneau, F. Lacreta, S. Cheng and E. Sultan, Clopidogrel pharmacodynamics and pharmacokinetics in the fed and fasted state: a randomized crossover study of healthy men, Clin. Pharmacol. 52 (2012) 1506-1515; DOI: 10.1177 /0091270011419852.
12. European Medicines Agency, Committee for Proprietary Medicinal Products (CPMP), ICH Topic E6 (R1), Guideline for good clinical practice, Step 5, Note for guidance on good clinical practice, CPMP/ICH/135/95, July 2002; http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000429.jsp&mid=WC0b01ac0580029590; access date April 22, 2013.
13. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, Off. J. Eur. Communities L Legis. L121 (2001) 34-44; http://ec.europa.eu/ health/documents/eudralex/vol-1/; access date April 22, 2013.
14. Commission directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. Off. J. Eur. Communities L Legis. L159 (2003) 46-94; http://ec.europa.eu/health/documents/eudralex/vol-1/; access date April 22, 2013.
15. World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects, 59th WMA General Assembly, October 2008; http://www.wma.net/ en/30publications/10policies/b3/; access date April 22, 2013.
16. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). Guidance for Industry, Bioanalytical Method Validation, May 2001; www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf; access date April 22, 2013.
17. D. Taubert, A. Kastrati, S. Harlfinger, O. Gorchakova, A. Lazar, N. von Beckerath, A. Schömig and E. Schömig, Pharmacokinetics of clopidogrel after administration of a high loading dose, Thromb. Haemost. 92 (2004) 311-316; DOI: 10.1160/TH04-02-0105.
18. N. von Beckerath, D. Taubert, G. Pogatsa-Murray, E. Schömig, A. Kastrati and A. Schömig, Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel, results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial, Circulation 112 (2005) 2946-2950; DOI: 10.1161/?CIRCULATIONAHA.105.559088.
19. D. Taubert, N. von Beckerath, G. Grimberg, A. Lazar, N. Jung, T. Goeser, A. Kastrati, A. Schömig and E. Schömig, Impact of P-glycoprotein on clopidogrel absorption, Clin. Pharmacol. Ther. 80 (2006) 486-501; DOI: 10.1016/j.clpt.2006.07.007.
20. A. R. Shuldiner, J. R.O’Connell, K. P. Bliden, A. Gandhi, K. Ryan, R. B. Horenstein, C. M. Damcott, R. Pakyz, U. S. Tantry, Q. Gibson, T. I. Pollin, W. Post, A. Parsa, B. D. Mitchell, N. Faraday W. Herzog and P. A. Gurbel, Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy, JAMA. 26 (2009) 849-857; DOI: 10.1001/ jama.2009.1232.
21. J. L. Mega, S. L. Close, S. D. Wiviott, L. Shen, J. R. Walker, T. Simon, E. M. Antman, E. Braunwald and M. S. Sabatine, Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis, Lancet 376 (2010) 1312-1319; DOI: 10.1016/S0140-6736(10)61273-1.
22. T. Simon, C. Verstuyft,M.Mary-Krause, L. Quteineh, E. Drouet,N.Méneveau, P. G. Steg, J. Ferrières, N. Danchin and L. Becquemont, Genetic determinants of response to clopidogrel and cardiovascular events, N. Engl. J. Med. 360 (2009) 363-375; DOI: 10.1056/NEJMoa0808227.
23. W. C. Lau, L. A. Waskell, P. B. Watkins, C. J. Neer, K. Horowitz, A. S. Hopp, A. R. Tait, D. G. Carville, K. E. Guyer and E. R. Bates, Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction, Circulation 107 (2003) 32-37; DOI: 10.1161/ ?01.CIR.0000047060.60595.CC.
24. W. C. Lau, P. A. Gurbel, P. B. Watkins, C. J. Neer, A. S. Hopp, D. G. Carville, K. E. Guyer, A. R. Tait and E. R. Bates, Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance, Circulation 109 (2004) 166-171; DOI: 10.1161/01.CIR. 0000112378.09325.F9.
25. European Medicines Agency, Committee for Human Medicinal Products (CHMP), Questions & Answers: Positions on specific questions addressed to the pharmacokinetics working party, EMA/618604/2008 Rev. 7, February 2013; http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000370.jsp&mid=WC0b01ac0580032ec5; access date April 22, 2013.