0 (1.0, 1.1) 1.0 (1.0, 1.1) \( t_E_\hboxmax \) INR (h) 24.0 (8.0–36.0) 24.0 (4.0–36.0) E max INR (fraction) 1.7 (1.5, 1.9) 1.9 (1.6, 2.2) AUCINR (fraction × h) 38.5 (30.1, 49.2) 38.8 (30.9, 48.8) Baseline factor VII (%) 82.6 (70.7, 96.5) 86.9 (71.3, 106) \( t_E_\hboxmax \) factor VII (h) 36.0 (24.0–36.0) 24.0 (24.0–36.0) E max factor VII (%) 16.1 (12.1, 21.4) 17.1 (12.7, 23.1) AUCfactor VII (% × h) 3,368 (2,676, 4,241) 3,281 (2,226, 4,835) Data are geometric means (and 95 % confidence limits) or, for selleck kinase inhibitor t max, the

median (and range) AUC area under the plasma concentration–time curve,

E max maximum effect, INR find more international normalized ratio Following administration of warfarin, both in the absence and presence of almorexant, factor VII concentrations decreased (Fig. 3). The maximum decrease occurred 24–36 h after administration, and factor VII slowly returned to baseline thereafter. The pharmacodynamic analysis appeared to show a difference in the time to E max between treatments, i.e., 36 h for treatment A and 24 h for treatment B, whereas other variables were similar (Table 3). Fig. 3 Arithmetic mean (and standard Selleckchem MLN0128 deviation) plasma concentration–time Progesterone profile of factor VII after administration of a single dose of 25 mg warfarin alone (treatment B) and in the presence of almorexant 200 mg once daily for 10 days with a single dose of 25 mg warfarin on day 5 (treatment A) to healthy male subjects (n = 13) 4 Discussion Almorexant is a dual orexin receptor antagonist and has been shown in vitro to inhibit CYP2C9, CYP2D6, and CYP3A4 (Actelion Pharmaceuticals, data on file). The present study investigated the effects of almorexant on warfarin pharmacokinetics and pharmacodynamics

in a randomized, two-way crossover study. Such a design reduces variability as each subject serves as his own control, thereby reducing the number of subjects to be included and is in accordance with current guidelines for in vivo interaction studies [20]. Warfarin was administered when almorexant concentrations were in steady state and any possible inhibition of CYP isoenzymes was maintained during the elimination phase of warfarin by continued administration of almorexant. The pharmacokinetics of warfarin in the absence of almorexant were in good agreement with previously reported results [19, 21].