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DOI: 10.1055/s-0033-1337931
Bioequivalence of Fixed Dose Combination of Atorvastatin 10 mg and Aspirin 150 mg Capsules: A Randomized, Open-Label, Single-Dose, Two-way Crossover Study in Healthy Human Subjects
Publication History
received 28 August 2012
accepted 31 January 2013
Publication Date:
22 March 2013 (online)
![](https://www.thieme-connect.de/media/drugres/201305/lookinside/thumbnails/10.1055-s-0033-1337931-1.jpg)
Abstract
The present study evaluated the bioavailability and bioequivalence of fixed dose combination test formulation (atorvastatin 10 mg and aspirin 150 mg capsule) against marketed reference formulations (Lipitor® tablets 10 mg and Nu-Seals tablets 75 mg). This study was an open label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover trial in 80 healthy adult human volunteers under fasting conditions. Plasma concentrations of atorvastatin, aspirin and salicylic acid were quantified using LC-MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental model and mean pharmacokinetic parameters were comparable between test and reference formulations. The mean pharmacokinetic parameters (AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞) for atorvastatin test and reference formulations were (52.69 ng.h/mL, 55.64 ng.h/mL, 9.45 ng/mL, 0.18 1/h and 0.17 1/h) and (52.20 ng.h/mL, 55.38 ng.h/mL, 10.25 ng/mL, 0.20 1/h and 0.19 1/h) respectively; and for aspirin were (1 378.62 ng.h/mL, 1 383.90 ng.h/mL, 1 022.18 ng/mL, 0.75 1/h and 0.75 1/h) and (1 314.17 ng.h/mL, 1 314.50 ng.h/mL, 985.90 ng/mL, 0.75 1/h and 0.75 1/h) respectively. Where as for salicylic acid, above parameters were (42 357.57 ng.h/mL, 44 139.47 ng.h/mL, 9 820.15 ng/mL, 0.24 1/h and 0.23 1/h) and (40 217.08 ng.h/mL, 42 032.44 ng.h/mL, 9 569.18 ng/mL, 0.24 1/h and 0.24 1/h) respectively for test and reference formulations. The 90% confidence intervals of atorvastatin and salicylic acid for AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞ parameters were found to be within the acceptable regulatory bioequivalence limits. In conclusion, the new fixed dose combination test formulation was bioequivalent to the reference formulations under fasting conditions.
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References
- 1 Poli A. Atorvastatin: pharmacological characteristics and lipid-lowering effects. Drugs 2007; 67: 3-15
- 2 Malhotra HS, Goa KL. Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia. Drugs 2001; 61: 1835-1881
- 3 Lipitor (atorvastatin) prescribing information. Parke-Davis, Division of Pfizer Inc, NY, NY 10017, revised Feb 2012
- 4 Mason RP, Walter MF, Day CA et al. Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism. J Biol Chem 2006; 281: 9337-9345
- 5 Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003; 110: 255-258
- 6 Fuster V, Sweeny JM. Aspirin: a historical and contemporary therapeutic overview. Circulation 2011; 123: 768-778
- 7 Levy G. Clinical pharmacokinetics of aspirin. Pediatrics 1978; 62: 867-872
- 8 Higgs GA, Salmon JA, Henderson B et al. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity. Proc Natl Acad Sci U S A 1987; 84: 1417-1420
- 9 Hennekens CH. Fixed-dose combination therapy with statins: strengths, limitations, and clinical and regulatory considerations. Am J Cardiovasc Drugs 2008; 8: 155-160
- 10 World Health Organization Technical Report Series . WHO Expert Committee on Specifications for Pharmaceutical Preparations. 39th report. Annex 5: Guidelines for registration of fixed-dose combination medicinal products. No. 929. Geneva: 2005 . [online]. Available from URL: http://apps.who.int/prequal/info_general/documents/TRS929/WHO_TRS_929_annex5FDCs.pdf
- 11 Hennekens CH, Hollar D, Agatston AS. Aspirin and statins to decrease risks of cardiovascular disease – the need for wider utilization. US Cardiology 2004; 1: 43-44
- 12 Athyros VG, Mikhailidis DP, Papageorgiou AA et al. Effect of statins and aspirin alone and in combination on clinical outcome in dyslipidaemic patients with coronary heart disease. A subgroup analysis of the GREACE study. Platelets 2005; 16: 65-71
- 13 Nakamura K, Masuda H, Kariyazono H et al. Effects of atorvastatin and aspirin combined therapy on inflammatory responses in patients undergoing coronary artery bypass grafting. Cytokine 2006; 36: 201-210
- 14 Santos MT, Fuset MP, Ruano M et al. Effect of atorvastatin on platelet thromboxane A 2 synthesis in aspirin-treated patients with acute myocardial infarction. Am J Cardiol 2009; 104: 1618-1623
- 15 Deputy Minister of Health and Social Development of the Russian Federation Drugs Bioequivalence Estimation. Moscow, 2008. Available at: https://doc-14-14-docsviewer.googleusercontent.com/viewer/securedownload/dsn1aovipa7l846lsfcf94nedj8q2p4u/iqom1b5i0gs9kdapj93equpnp1lrr8st/1345366800000/ZXhwbG9yZXI=/AGZ5hq8BgbJY1gwaOYx83cPOdNw6/MEIzVVc2dDRHS3gxellqRm1PVGMxTjJVdE5tVXhOUzAwWlRkaExUZzFPVEl0WlROa1lUVXlZamhrWVdVNQ==?docid=bdb7c64ccd37f4e9692ac2ed31ffcd80%7C5954fa4e781a9ec8408ae6545feef37c&chan=EQAAANE%2Bfe1RmC58OLC69WmQ4j35Yb%2Bz3E59gZTrCmdHGKFt&sec=AHSqidbsnqrZAPbmsXcRDs_mPzF59QRQgTlPXzsUfYngpN14NJniouBz2GW2D0_v3qz79ZpY8jhY&a=gp&filename=Russian+BE+guidance+2008_english.pdf&nonce=m5kpvlefmannk&user=AGZ5hq8BgbJY1gwaOYx83cPOdNw6&hash=eb55tge4ofrmos9nlh6148k42s8cdg5o
- 16 Chen ML, Shah V, Patnaik R et al. Bioavailability and bioequivalence: an FDA regulatory overview. Pharm Res 2001; 18: 1645-1650
- 17 Bukhari NI, Zafar A, Shamsi WR et al. Bioequivalence assessment of two enteric-coated aspirin brands, Nu-Seals and Loprin, after a single oral dose of 150 mg in healthy male adults. Therapie 2005; 60: 167-173
- 18 Macwan JS, Ionita IA, Dostalek M et al. Development and validation of a sensitive, simple, and rapid method for simultaneous quantitation of atorvastatin and its acid and lactone metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Anal Bioanal Chem 2011; 400: 423-433
- 19 Borek-Dohalský V, Huclová J, Barrett B et al. Validated HPLC-MS-MS method for simultaneous determination of atorvastatin and 2-hydroxyatorvastatin in human plasma-pharmacokinetic study. Anal Bioanal Chem 2006; 386: 275-285
- 20 Xu X, Koetzner L, Boulet J et al. Rapid and sensitive determination of acetylsalicylic acid and salicylic acid in plasma using liquid chromatography-tandem mass spectrometry: application to pharmacokinetic study. Biomed Chromatogr 2009; 23: 973-979
- 21 Nirogi R, Kandikere V, Mudigonda K et al. Simultaneous extraction of acetylsalicylic acid and salicylic acid from human plasma and simultaneous estimation by liquid chromatography and atmospheric pressure chemical ionization/tandem mass spectrometry detection. Application to a pharmacokinetic study. Arzneimittelforschung 2011; 61: 301-311
- 22 Kandhwal K, Dey S, Nazarudheen S et al. Pharmacokinetics of a fixed-dose combination of atorvastatin and metformin extended release versus concurrent administration of individual formulations: a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study. Clin Drug Investig 2011; 31: 853-863
- 23 Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 2003; 42: 1141-1160
- 24 Lins RL, Matthys KE, Verpooten GA et al. Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant 2003; 18: 967-976
- 25 Gandelman K, Fung GL, Messig M et al. Systemic Exposure to Atorvastatin Between Asian and Caucasian Subjects: A Combined Analysis of 22 Studies. Am J Ther 2012; 19: 164-173
- 26 Narwal R, Akhlaghi F, Asberg A et al. Development of a population pharmacokinetic model for atorvastatin acid and its lactone metabolite. Clin Pharmacokinet 2010; 49: 693-702
- 27 Gandelman K, Malhotra B, LaBadie RR et al. Analytes of interest and choice of dose: two important considerations in the design of bioequivalence studies with atorvastatin. J Bioequiv Availab 2011; 3: 62-68
- 28 Lipitor (Atorvastatin) clinical pharmacology and biopharmaceutics review, NDA: 20-702, Page no. 250 of 373. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020702_s000.pdf