Clopidogrel does not affect the pharmacokinetics of theophylline

The potential influence of clopidogrel on the pharmacokinetics of theophylline was evaluated in 15 healthy male subjects during the pharmacokinetic steady state of theophylline, after single and multiple doses. Theophylline was administered orally as one 300-mg capsule in the morning before breakfast and one in the evening before dinner for 13 days (day 1 through day 13), and one capsule on the morning of day 14. Clopidogrel was administered orally as one 75-mg tablet in the morning before breakfast from day 5 through day 14. Plasma concentration of theophylline was determined at the following times: before the morning dose on days, 1, 6-9, and 12; before administration, then at 0.5, 1,2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after administration on days 4, 5, and 14. Tests of hemostasis (ADP-induced platelet aggregation and bleeding time) were carried out 2 hours after clopidogrel dosing on days 5, 7, 9, 11, and 14. The curves of the mean plasma concentration of theophylline over 12 hours post-morning dose on day 4 (drug alone), day 5 (after a single dose of clopidogrel), and day 14 (after 10 days of clopidogrel coadministration) were superimposable, indicating the absence of an effect of clopidogrel on the steady-state pharmacokinetics of theophylline. There were no statistically significant differences between the days of administration for the log-transformed values of theophylline C(bt) (concentration before treatment) Cmax, AUC(0-12h), and Cmin; and the 90% confidence intervals of the day 5/day 4, day 14/day 4, and day 14/day 5 ratios of the geometric means of C(bt) all fell within the (0.80; 1.25) interval. These results show that the administration of clopidogrel during steady state theophylline administration had no effect on the plasma concentration of the latter drug. The average steady-state (days 11-14) percentage of inhibition of ADP-induced platelet aggregation by clopidogrel with respect to day 1 was 46%. The geometric mean of the bleeding time prolongation factor was about 2 at steady state. The latter results indicate that the pharmacodynamics of clopidogrel were not affected by concomitant theophylline.