Clopidogrel, a novel antiplatelet agent, and digoxin: Absence of pharmacodynamic and pharmacokinetic interaction

The safety, and the pharmacodynamic and pharmacokinetic compatibility of cl opidogrel, 75 mg daily, with the cardiac glycoside digoxin, were assessed i n 12 healthy male subjects who took digoxin 0.25 mg once daily for 20 days and, in addition, clopidogrel 75 mg once daily from day 11 to day 20, so as to achieve steady-state conditions with both drugs. The drugs were taken a fter an overnight fast, and a standardized breakfast was served 30 minutes later. Blood samples for digoxin determination were drawn predose on days 1 , 8, 9, 10, 18, 19, and 20 of the schedule, and at 0.5, 1, 2, 3, 4, 5, 6, 8 , 12, 16, and 24 hours postdose on days 10 and 20, Urine samples were colle cted pre-dose and from 0-4, 4-8, 8-12, and 12-24 hours post-dose on days 10 and 20. Platelet aggregation studies were carried out using ADP at 5 mu mo l/L final concentration as an agonist. Establishment of steady-state plasma concentrations of digoxin on days 8-11 and 18-21 was confirmed by applicat ion of Dunnett's test on the trough plasma concentrations. The plasma pharm acokinetics and urinary excretions of digoxin for day 10 and day 20 were ve ry similar: the day 20/day 10 ratios (90% CI) were 1.1 (0.99; 1.24) for C-m ax, 1.0 (0.92; 1.08) for C-min, 1.02 (0.96; 1.07) for AUC(0-24), and 0.99 ( 0.94; 104) for urinary excretion. Mean inhibition of ADP-induced platelet a ggregation at the end of the clopidogrel treatment period was 34%. The clin ical, cardiac, and biological evidence from the study indicated that clopid ogrel administration does not enhance digoxin's cardiac effects. Overall, t he data indicated that there is no reason to anticipate an interaction when clopidogrel is added to digoxin for long-term management of patients with cardiac disease.