Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Ximelagatran in Young Healthy Japanese Men

Abstract

The direct thrombin inhibitor ximelagatran, which is rapidly bioconverted to its active form melagatran after oral administration, is being developed for the prevention and treatment of thromboembolism. This study assessed the effects of food and repeated dosing on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran to young healthy Japanese males. In part one of the two-part study, volunteers (n = 24) were randomised to receive in a crossover fashion a single oral dose of ximelagatran 48mg with or without breakfast on 2 days separated by a 2- to 7-day washout period. In the second part of the study, all volunteers received oral doses of ximelagatran 48mg every 12 hours for 5 days followed by a single dose on the morning of day 6. The area under the plasma concentration-time curve (AUC), peak plasma concentration (C(max)) and urinary excretion of melagatran did not differ as a function of whether ximelagatran was taken with or without food. The relationship between the melagatran plasma concentration and activated partial thromboplastin time (aPTT, which reflects the thrombin inhibitory effect of melagatran) was also independent of concomitant food intake. During repeated dosing, steady-state plasma concentrations of melagatran were achieved after the second dose of ximelagatran on day 1 and remained stable through the rest of the dosing period. The melagatran AUC and C(max) increased slightly (by 18% and 22%, respectively) on day 6 compared with day 1. The interindividual variability in the melagatran AUC and C(max) remained low, as reflected by coefficients of variation of <20% on both day 1 and day 6. The amount of melagatran excreted in urine remained stable over the 6 days of repeated dosing. The pharmacokinetics, pharmacodynamics, safety and tolerability of melagatran after oral administration of ximelagatran were not affected by food or repeated dosing in healthy Japanese volunteers.