Influence of Age on the Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor

Abstract

Objective: To investigate the influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran. Study design: This was an open-label, randomised, 3 × 3 crossover study with 4 study days, separated by washout periods of 7 days. Subjects: Subjects comprised 6 healthy young men (aged 20–27 years) and 12 healthy older men and women (aged 56–70 years). Methods: All subjects received a 2mg intravenous infusion of melagatran over 10 minutes followed, in randomised sequence, by a 20mg immediate-release tablet of ximelagatran with breakfast, a 20mg immediate-release tablet of ximelagatran while fasting, and a 7.5mg subcutaneous injection of ximelagatran. The primary variables were the plasma concentration of melagatran, the active form of ximelagatran, and the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin. Results: After oral and subcutaneous administration, ximelagatran was rapidly absorbed and biotransformed to melagatran, 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 ximelagatran. Clearance of melagatran was correlated with renal function, resulting in about 40% (after intravenous melagatran) to 60% (after oral and subcutaneous ximelagatran) higher melagatran exposure in the older than in the young subjects. Renal clearance of melagatran, determined after intravenous administration of melagatran, was 7.7 L/h and 4.9 L/h in the young and older subjects, respectively. The interindividual variability in the area under the melagatran plasma concentration-time curve was low following all regimens (coefficient of variation 12–25%). The mean bioavailability of melagatran in young and older subjects was approximately 18 and 21%, respectively, following oral administration of ximelagatran, and 38 and 45%, respectively, following subcutaneous administration of ximelagatran. The bioavailability of melagatran following oral administration of ximelagatran was unaffected by whether subjects were fed or fasting, although the plasma concentration of melagatran peaked about 1 hour later under fed than fasting conditions, due to delayed gastric emptying of the immediate-release tablet formulation used. The APTT was prolonged with increasing melagatran plasma concentrations and the concentration-effect relationship was independent of age. Conclusion: There were no age-dependent differences in the absorption and biotransformation of ximelagatran, and the observed differences in exposure to melagatran can be explained by differences in renal function between the young and older subjects.