Objective: Fondaparinux sodium is the first of a new class of antithrombotic agents: the selective factor Xa inhibitors. Coadministration with digoxin may occur in clinical practice and both drugs are excreted almost completely by the renal route. In this study we assessed the possible pharmacokinetic and pharmacodynamic interaction of fondaparinux sodium with digoxin at steady state in healthy male volunteers.
Design: In a phase I randomised, crossover study, volunteers (n = 24) were treated in two periods. The first period was once-daily administration of fondaparinux sodium 10mg subcutaneously alone for 7 days; the second period was 7 days of digoxin 0.25mg orally alone followed by 7 days of coadministration with fondaparinux sodium 10mg. Each period was separated by a washout of 12 days.
Methods: Urinary volumes, plasma concentration-time profiles and noncompartmental pharmacokinetic parameters of fondaparinux sodium and digoxin were obtained at steady state, following administration alone or together for each period. A bioequivalence approach was taken to assess interaction. Pharmacodynamic parameters were supine blood pressure and heart rate and the ECG parameters PR interval, QRS interval, QT interval and QT(c). The safety of the treatments was monitored.
Results and conclusions: The pharmacokinetic profiles of both digoxin and fondaparinux sodium were unaffected by coadministration. Bioequivalence was concluded, based on the 90% confidence intervals of the ratio of adjusted geometric means calculated for the 2-by-2 comparison of peak concentration, area under the concentration-time curve and cumulative urinary excretion, which lay within the 0.80 to 1.25 reference interval. There were no clinically significant fluctuations in vital signs and ECG parameters. The coadministration of digoxin with fondaparinux sodium was well tolerated and no significant changes were observed in vital signs.