Influence of age on the pharmacokinetics and pharmacodynamics of @entity24772 , an oral direct XXXX inhibitor.

@entity1 @entity18422 @entity556 @entity24772
OBJECTIVE: To investigate the influence of age on the pharmacokinetics and pharmacodynamics of @entity24772 . STUDY DESIGN: This was an open-label, randomised, 3 x 3 crossover study with 4 study days, separated by washout periods of 7 days. SUBJECTS: Subjects comprised 6 healthy young @entity1 (aged 20-27 years) and 12 healthy older @entity1 and @entity1 (aged 56-70 years). METHODS: All subjects received a 2mg intravenous infusion of @entity18422 over 10 minutes followed, in randomised sequence, by a 20 mg immediate-release tablet of @entity24772 with breakfast, a 20 mg immediate-release tablet of @entity24772 while fasting, and a 7.5 mg subcutaneous injection of @entity24772 . The primary variables were the plasma concentration of @entity18422 , the active form of @entity24772 , and the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of @entity556 . RESULTS: After oral and subcutaneous administration, @entity24772 was rapidly absorbed and biotransformed to @entity18422 , its active form and the dominant compound in plasma. The metabolite pattern in plasma and urine was similar in young and older subjects after both oral and subcutaneous administration of @entity24772 clearance of @entity18422 was correlated with renal function, resulting in about 40% (after intravenous @entity18422 ) to 60% (after oral and subcutaneous @entity24772 ) higher @entity18422 exposure in the older than in the young subjects. Renal clearance of @entity18422 , was 7.7 L/h and 4.9 L/h in the younger and older subjects, respectively. The interindividual variability inn the area under the @entity18422 plasma concentration-time curve was low following all regimens (coefficient variation 12-25%). The mean bioavailability of @entity18422 in young and older subjects was approximately 18 and 12% , respectively, following oral administration of ximalagratan, and 38 and 45%, respectively, following subcutaneous administration of @entity24772 . The bioavailability of @entity18422 following oral administration of @entity24772 was unaffected by whether subjects were fed or fasting, although the plasma concentration of @entity18422 peaked about 1 hour later under fed than fasting conditions, due to gastric emptying of the immediate-release tablet formulation used. The APTT as prolonged with increasing @entity18422 plasma concentration-effect relationship was independent of age. CONCLUSIONS: There were no age-dependent differences in the absorption and biotransformation of @entity24772 , and the observed differences in exposure to @entity18422 can be explained by differences in renal function between the young and older subjects.
