POPULATION PHARMACOKINETIC-PHARMACODYNAMIC ANALYSIS OF FLUINDIONE IN PATIENTS

Objective: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharm acodynamics of multiple doses of fluindione in patients. Methods:In a learning group of 49 patients who began fluindione treatment, blood sa mples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of dotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalize d ratio (INR) were measured. An indirect-response pharmacodynamic mode l was used for each effect. A comprehensive analysis was performed wit h a nonparametric population approach. The model was evaluated in 24 o ther patients: blood samples were taken 24 hours after two, three, fou r, and six doses; and PCA and INR were observed. Results: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentrat ion that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for fa ctors VII and II, respectively. The results obtained for INR and PCA w ere validated in the 24 subsequent patients. Conclusion: The populatio n approach allowed the comparison of several pharmacodynamic submodels . This first application of the indirect-response model to multiple or al anticoagulant doses in patients confirmed that both the pharmacokin etics and the pharmacodynamics of fluindione show substantial interind ividual variability.