The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant activity of warfarin in healthy volunteers

Aims The aims of this study were to determine the effects of the nonsteroid al, selective aromatase inhibitor, anastrozole, at steady-state concentrati ons, on the pharmacokinetics and pharmacodynamics of warfarin, and to asses s whether or not anastrozole alone has any anticoagulant activity. Methods This was a randomized, double-blind, placebo-controlled, two-way cr ossover trial conducted at a single centre. The study comprised two treatme nt periods of 11 days, separated by a 3 week washout. Healthy male voluntee rs (n = 16, median age 28.5 years) were randomized to receive either anastr ozole (7 mg loading dose on day 1, followed by 1 mg daily on days 2-11) in the first treatment period and placebo in the second treatment period, or v ice vena. In addition to their randomized treatment, all volunteers receive d a single dose of 25 mg warfarin on day 3 of each treatment period. Blood samples for pharmacokinetic and pharmacodynamic assessment were taken at fr equent intervals during each treatment period. The safety of volunteers was monitored throughout the study. Results Administration of anastrozole resulted in no clinically significant changes in the pharmacokinetics of either R- or S-warfarin compared with p lacebo for AUC (ng ml(-1) h) (glsmean, R-warfarin; anastrozole 93619.9, pla cebo 91127.91, 95%CI 0.988-1.068; S-warfarin; anastrozole 57129.21, placebo 55676.34, 95%CI 0.979-1.076), CL/F (ml min(-1)) (glsmean, R-warfarin; anas trozole 2.23, placebo 2.29, 95%CI 0.937-1.012; S-warfarin; anastrozole 3.65 , placebo 3.74, 95%CI 0.929-1.021) and t(1/2) (h) (1smean, R-warfarin; anas trozole 55.40, placebo 55.15, 95%CI-2.083-2.592; S-warfarin; anastrozole 39 .38, placebo 40.98, 95%CI-6.189-2.996). In addition, anastrozole had no cli nically significant effect on the pharmacodynamic effects of warfarin, as a ssessed 240 h after warfarin dosing by measurement of prothrombin time (s) (glsmean, anastrozole 11.56, placebo 11.31, 95%CI 0.987-1.059), thrombin ti me (s) (glsmean, anastrozole 19.06, placebo 18.75, 95%CI 0.980-1.054) activ ated partial thromboplastin time (s) (glsmean, anastrozole 29.94, placebo 2 9.74, 95%CI 0.968-1.047) and factor VII (%) (glsmean, anastrozole 97.81, pl acebo 107.26, 95%CI 0.821-1.012). Anastrozole alone had no effect on these indicators of the clotting process. Conclusions Overall, there was no evidence to suggest that anastrozole has any clinically relevant effects on the pharmacokinetics of warfarin. Anastr ozole had no effect on clotting mechanisms or on the pharmacodynamic activi ty of warfarin, as assessed by prothrombin time, thrombin time, activated p artial thromboplastin time, and factor VII.