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The pharmacokinetics of idraparinux, a long‐acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials

Summary.  Background: Idraparinux, a long‐acting synthetic pentasaccharide, is a specific antithrombin‐dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once‐weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min−1). A population pharmacokinetic model was developed using data from 704 patients with acute deep‐vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three‐compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady‐state were 0.0255 L h−1, 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half‐life was 66.3 days and time to steady‐state was 35 weeks. At steady‐state, exposures were similar for patients without and with severe renal impairment receiving adjusted‐dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux – rapid onset of action and long‐acting anticoagulant effect – offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux.