A Phase I study to characterize the multiple-dose pharmacokinetics, pharmacodynamics and safety of new enteric-coated triflusal formulations in healthy male volunteers

Abstract

Objectives: An enteric-coated formulation of triflusal (triflusal EC), an antiplatelet agent, was developed to reduce the high incidence of gastrointestinal adverse events (AEs). The aim of this study is to compare the pharmacokinetics, pharmacodynamics and safety of triflusal EC with triflusal in healthy Korean male subjects to determine bioequivalence and non-inferiority for the purposes of marketing approval.

Methods: A randomized, open-label, two-period, crossover study was conducted in 38 subjects. Either triflusal EC or triflusal was administered orally as a single 900 mg loading dose (day 1) followed by eight 600 mg/day maintenance doses on days 2 – 9, with a 13-day washout period. The plasma concentrations of 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), the predominant active metabolite of triflusal, were assessed after administration of the loading dose, using HPLC/MS/MS. The platelet aggregation response to arachidonic acid was determined using turbidimetric aggregometry.

Results: The 90% CIs, for the geometric mean ratios of the log-transformed AUC_τ and C_max of HTB were seen to be within the predetermined range of 0.8 – 1.25. Triflusal EC was also shown to be non-inferior in its anti-aggregatory effect. No serious AEs were reported during this study.

Conclusions: The pharmacokinetic and pharmacodynamic profiles of the two triflusal formulations met the requirements for bioequivalence and non-inferiority, respectively. Both formulations were well tolerated.

Keywords:

• enteric-coated formulation
• pharmacokinetics
• platelet aggregation
• triflusal

Acknowledgements

The authors thank Jung-Uk Lee and Hang-Myung Lee of Myung-In Pharm. Co. Ltd for their comments. The authors also thank R Turner of Textcheck, FL, USA, who edited the manuscript. There is some overlap (in part) between this manuscript and an abstract that was presented (poster) in the 2011 ASCPT annual meeting (2 – 5 March 2011, Dallas, TX, USA).

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