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DOI: 10.1055/s-0032-1316290
Bioequivalence of Acenocoumarol in Chilean Volunteers: an Open, Randomized, Double-Blind, Single-Dose, 2-Period, and 2-Sequence Crossover Study for 2 Oral Formulations
Publication History
received 22 March 2012
accepted 26 May 2012
Publication Date:
06 July 2012 (online)
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Abstract
The aim of this study was to compare the bioavailability of an oral formulation of the coumarin derivative-vitamine K antagonist acenocoumarol (AcebronTM 4 mg, Test) with the reference formulation (Neo-SintromTM 4 mg). We performed a single-dose, double-blind, fasting, 2-period, 2-sequence, crossover study design. Plasma concentrations of acenocoumarol were determined using a validated UPLC-MS/MS method. 24 healthy Chilean volunteers (11 male, 13 female) were enrolled and all of them completed the study. Adverse events were monitored throughout the study. The values of the pharmacokinetic parameters were (mean ± SD): AUC0-24 =1 364.38±499.26 ngxh/mL for the test and 1 328.39±429.20 ngxh/mL for the reference; AUC0-∞ =1 786.00±732.85 ngxh/mL for the test and 1 706.71±599.66 ngxh/mL for the reference; Cmax =180.69±35.11 ng/mL with a Tmax of 1.83±0.95 h for the test and 186.97±38.21 ng/mL with a Tmax of 2.19±0.83 h for the reference. Regarding half life measurements, the mean ± SD of t1/2 were 11.84±4.54 h for the test and 11.08±3.28 h for the reference. The 90% confidence intervals for the test/reference ratio using logarithmic transformed data were 97.89–100.87%, 98.62–101.99% and 98.64–102.38% for Cmax, AUC0-t(24) and AUC0–∞. There were no significant differences in pharmacokinetic parameters between groups.
The results obtained in this study lead us to conclude, based on FDA criteria, that the test acenocoumarol formulation (AcebronTM, 4 mg tablets) is bioequivalent to the reference product (Neo-SintromTM, 4 mg tablets).
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References
- 1 Ulfer M. Comparative Pharmacokinetics of vitamin k antagonists: warfarin, phenprocoumon and acenocoumarol. Clin. Pharmacokinetic 2005; 44: 1227-1246
- 2 Gadisseur AP, van der Meer FJ, Adriaansen HJ et al. Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon. British Journal of Haematology 2002; 117: 940-946
- 3 Vecchione G, Casetta B, Tomaiuolo M et al. A rapid method for the quantification of the enantiomers of Warfarin, Phenprocoumon and Acenocoumarol by two-dimensional-enantio-selective liquid chromatography/electrospray tandem mass spectrometry. J Chromatogr B. 2007; 850: 507-514
- 4 Brandjes DPM, Heijboer H, Buller HR et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327: 1485-1489
- 5 Acenocumarol . In Formulario Nacional de Medicamentos DTO. 194/2005 Gobierno de Chile, Ministerio de Salud 2006; 223-224
- 6 Drug Information Online. http://www.drugs.com/mmx/acenocoumarol.html . Accessed March 07, 2012
- 7 Dieterle W, Faigle JW, Montigel C et al. Biotransformation and pharmacokinetics of acenocoumarol (Sintrom) in man. Eur J Clin Pharmacol 1977; 11 (05) 367-375
- 8 Popović J, Mikov M, Jakovljević V. Pharmacokinetic analysis of a new acenocoumarol tablet formulation during a bioequivalence study. Eur J Drug Metab Pharmacokinet 1994; 19 (02) 85-89
- 9 Saavedra I. Conceptos de farmacodinamia y farmacocinética en la perspectiva clínica. En Rosselot E, Biagini L. (eds.). Farmacología Clínica en Medicina Interna. Series Clínicas Sociedad Médica de Santiago; Editorial Mediterráneo: 1987. Vol. VII (1): 15-20
- 10 Saavedra I, Saldaña A, Ruminot C.. Medicamentos Genéricos. Cuadernos Médicos Sociales 2006; 46 (03) 205-211
- 11 Multisource (Generic) Pharmaceuticals Products . Guidelines on Registration Requirements to Establish Interchangeability, WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva: 2006
- 12 BMJ . NUREMBERG DOCTORS’ TRIAL Declaration of Helsinki 7 December ed Vol. 313 1996; 1448-1449
- 13 FDA . Guidance for Industry. “E6 Good Clinical Practice: consolidate guidance” U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research; April 1996;
- 14 Huang C, Yang J, Du Y et al. Measurement of free concentrations of highly protein-bound Warfarin in plasma by ultra performance liquid chromatography-tandem mass spectrometry and its correlation with the international normalized ratio. Clin Chim Acta 2008; 393 (02) 85-89
- 15 STATA Corporation intercooler for Windows, college station, TX V 10, 2007
- 16 FDA. Guidance for Industry Statistical Approaches to Establishing Bioequivalence U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); January 2001;
- 17 FDA. Guidance for Industry. BA and BE Studies for Orally Administered Drug Products-General Considerations, US. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); 2003;
- 18 Code of federal Regulations . Title 21, part.320. “Bioavailability and bioequivalence Requirements”. Washington: 1998
- 19 Schuirman DJ. A comparison of the two on-sided tests procedure and the power Approach for assessing the bioequivalence of average bioavailability. J Pharmacokinetics Biopharm 1987; 15: 657-680
- 20 Schuirmann DJ. On hypothesis testing to determine if the mean of a normal distribution is contained in a known interval. Biometrics 1981; 37: 617
- 21 Laosa O, Guerra P, Durán-López J. Estudios de bioequivalencia: la necesidad de establecer la fiabilidad de los medicamentos genéricos. Rev Perú Med Exp Salud Pública 2009; 26 (04) 553-562
- 22 Resolución exenta 05937. Establece productos de referencia para estudios de bioquivalencia de productos farmacéuticos monodroga de liberación inmediata. 31 Diciembre de 2009. Instituto de Salud Pública de Chile (ISP)
- 23 Godbillon J, Richard J, Gerardin A et al. Pharmacokinetics of the enantiomers of acenocoumarol in man. Br J Clin Pharmacol 1981; 12: 621-629
- 24 Meinertz T, Kasper W, Kahl C et al. Anticoagulant activity of the enantiomers of acenocoumarol. Br J Clin Pharmacol 1978; 5: 187-188
- 25 Katharina R. The importance of stereo selective determination of drugs in the clinical laboratory. J Biochem Biophysics Methods 2002; 54: 1-9
- 26 Rentsch K, Gutteck-Amsler U, Bührer R et al. Sensitive stereospecific determination of acenocoumarol and phenprocoumon in plasma by high-performance liquid chromatography. Journal of Chromatography B 2002; 742: 131-142
- 27 Wong LT, Solomonraj G. Quantitation of acenocoumarol in plasma by reversed-phase high-performance liquid chromatography. Journal of Chromatography B. 1979; 163: 103-108
- 28 Pommier F, Ackermann R, Sioufi A et al. Determination of acenocoumarol in human plasma by capillary gas chromatography with mass-selective detection. Journal of Chromatography B. 1994; 654: 35-41
- 29 FDA. Guidance for Industry, Bioanalytical Method Validation. US Department of Health and Human Services, Food and Drug Administration. In CfVMC Center for Drug Evaluation and Research (CDER); May 2001;
- 30 Rolan P, Terpstra IJ, Clarke C. A placebo – controlled pharmacodynamic and pharmacokinetic interaction study between tamsulosin and acenocoumarol. Br J Clin Pharmacol 2003; 55 (03) 314-316
- 31 Pope N. Generic Substitution of Narrow. Therapeutic Index Drugs. US Pharm 2009; 34 (06) (Generic Drug Review suppl) 12-19