Comparative bioavailability study of triflusal oral solution vs. triflusal capsules in healthy subjectsA single, randomized, two-way cross-over, open-label phase I study

Iñaki Izquierdo; Javier Borja; Sandra Rovira; Pilar Pelagio; Ferran Torres; Jesus Cebrecos; Julián García-Rafanell

doi:10.1055/s-0031-1296246

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2010; 60(1): 36-41
DOI: 10.1055/s-0031-1296246

Anticoagulants · Antithrombotics · Antivaricosis Drugs · Blood Flow Stimulants

Editio Cantor Verlag Aulendorf (Germany)

Comparative bioavailability study of triflusal oral solution vs. triflusal capsules in healthy subjects
A single, randomized, two-way cross-over, open-label phase I study

Iñaki Izquierdo

¹Clinical Development Unit, J. Uriach y Compañía, S.A., Barcelona, Spain

,

Javier Borja

¹Clinical Development Unit, J. Uriach y Compañía, S.A., Barcelona, Spain

,

Sandra Rovira

²Phase I Unit. Laboratorio Dr. F. Echevarne análisis S.A, Barcelona, Spain

,

Pilar Pelagio

³Bioanalysis-Pharmacokinetic Unit, Laboratorio Dr. F. Echevarne análisis SA, Barcelona, Spain

,

Ferran Torres

⁴Laboratory of Biostatistics and Epidemiology (Universitat Autonoma de Barcelona), Barcelona, Spain

⁵Statistics and Methodology Support Unit, IDIBAPS, Hospital Clinic, Barcelona, Spain

,

Jesus Cebrecos

²Phase I Unit. Laboratorio Dr. F. Echevarne análisis S.A, Barcelona, Spain

,

Julián García-Rafanell

¹Clinical Development Unit, J. Uriach y Compañía, S.A., Barcelona, Spain

› Author Affiliations

Abstract

Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxy-genase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose.

This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bio-equivalence assessment included AUC_0–t, AUC_0–∞ and C_max. The formulations were considered bioequivalent if the geometric mean ratios of AUC_0–t, AUC_0–∞ and C_max were within the predetermined equivalence range (80% to 125%). Toler-ability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC_0–t (μg · h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC_0–∞ (μg · h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; C_max (μg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; C_max/AUC_0–∞ (h⁻¹): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC_0–∞, AUC_0–t, and C_max were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness.

It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulations were well tolerated.

Key words

Antiplatelet agents - CAS 322-79-2 - COX-1 inhibitors - Triflusal, bioavailability, capsule, oral solution

Full Text

References

References
1 JM Cruz-Fernández. Antiplatelet drugs in the treatment of acute coronary syndromes: Focus on Cyclooxigenase inhibitors. Eur Heart J. 2001; 3 (I) 123-30
2 Murdoch D, Plosker GL. Triflusal: a review of its use in cerebral infarction and myocardial infarction, and as throm-boprohylaxis in atrial fibrillation. Drugs. 2006; 66: 671-92
3 García-Rafanell J, Ramis J, Gómez L, Forn J. Effect of triflusal and other salicylic acid derivatives on cyclic AMP levels in rat platelets. Arch Int Pharmacodyn Ther. 1986; 284: 155-65
4 Cruz-Fernández JM, López-Bescos L, García-Dorado D, López García-Aranda V, Cabadés A, Martín-Jadraque L et al. Randomized comparative trial of Triflusal and aspirin following acute myocardial infarction. Eur Heart J. 2000; 21: 457-65
5 Matias-Guiu J, Ferro JM, Álvarez-Sabin J, Torres F, Jiménez MD, Lago A et al. Comparison of Triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke. 2003; 34: 840-8
6 Culebras A, Rotta-Escalante R, Vila J, Domínguez R, Abiusi G, Famulari A et al. Triflusal vs aspirin for prevention of cerebral infarction. Neurology. 2004; 62: 1073-80
7 Costa J, Ferro JM, Matias-Guiu J, Alvarez-Sabín J, Torres F et al. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev. 2005; 3: CD004296
8 Plaza L, López-Bescós L, Martín-Jadraque L, Alegría E, Cruz-Fernández JM, Velasco J et al. Protective effect of triflusal against acute myocardial infarction in patients with instable angina: results of a Spanish multicenter trial. Cardiology. 1993; 82: 388-98
9 Guiteras P, Altimiras J, Arís A, Augé JM, Bassons T, Bonal J et al. Prevention of aortocoronary vein-graft attrition with low-dose aspirin and triflusal, both associated with dipyridamole: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 1989; 10: 159-67
10 Aramendi JI, Mestres CA, Martinñz-Lñon J, Campos V, Muñoz G, Navas C et al. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bio prosthetic valve replacement (trac): prospective, randomized, co-operative trial. Eur J Cardio Thoracic Surg. 2005; 27: 854-60
11 Auteri A, Angaroni A, Borgatti E, Catalano M, De Vizzi GB, Forconi S et al. Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double-blind clinical study vs placebo. Int J Clin Pharm Res. 1995; XV: 57-63
12 Pérez-Gómez F, Alegría E, Berjón J, Iriarte A, Zumalde J, Salvador A et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation. J Am Coll Cardiol. 2004; 44: 1557-66
13 Lanas A, Serrano P, Bajador E, Fuentes J, Sáinz R et al. Risk of upper gastrointestinal bleeding associated with non-aspirin cardiovascular drugs, analgesics and nonsteroidal anti-inflammatory drugs. Eur J Gastroenterol Hepatol. 2003; 15: 173-8
14 Ibáñez L, Vidal X, Vendrell L, Moretti U, Laporte JR et al. Upper gastrointestinal bleeding associated with antiplatelet drugs. Aliment Pharmacol Ther. 2006; 23: 235-42
15 Fraj J, Valero A, Vives R, Pérez I, Borja J, Izquierdo I et al. Safety of triflusal (antiplatelet drug) in patients with aspirin-exacerbated respiratory diseases. Allergy. 2008; 63: 112-5
16 Adams Jr HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A et al. Guidelines for the early management of adults with ischemic stroke. Stroke. 2007; 38: 1655-711
17 Finiels H, Struble D, Jaquot JM. Les troubles de la déglutition du sujet âgé. Presse Med. 2001; 30: 1623-34
18 Meyboom RHB, Hekster YA, Egberts ACG, Gribnau FW, Edwards IR et al. Causal or casual?. The role of causality assessment in pharmacovigilance. Drug Saf. 1997; 17: 374-89
19 Christie B. Doctors revise declaration of Helsinki. Br Med J. 2000; 321: 913-
20 European Medicines Agency. Note for Guidance on Good Clinical Practice CPMP/ICH/135795. London;2002.
21 Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ et al. Bioanalytical method validation – a revisit with a decade of progress. Pharm Res. 2000; 17: 1551-7
22 EMEA. Note for guidance on the investigation of bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98. London;2001.
23 Wijnand HP. Updates of bioequivalence programs (including statistical power approximated by Student’s t). Computs Methods Program Biomed. 1995; 47: 93-4
24 Hauschke D, Steinijans VW, Diletti E. A distribution-free procedure for the statistical analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol. 1990; 28: 72-78
25 Wijnand HP. Updates of bioequivalence programs (including statistical power approximated by Student’s t). Comput Methods Programs Biomed. 1994; 42: 275-81
26 Meng NH, Wang TG, Lieng IN. Dysphagia in patients with brainstem stroke: incidence and outcome. Am J Phys Med Rehabil. 2000; 79: 170-5
27 The European Stroke Organisation (ESO) Executive Committee and the ESO Writing Committee Guidelines for management of ischemic stroke and transient ischemic attack 2008. Cerebrovasc Dis. 2008; 25: 457-507
28 Romano JG, Sacco RL. Progress in secondary stroke prevention. Ann Neurol. 2008; 63: 418-27
29 O’Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: A critical review. Stroke. 2008; 39: 1638-46