Objectives: Two studies were conducted to elucidate the pharmacokinetics and pharmacodynamics of melagatran after administration of the oral direct thrombin inhibitor ximelagatran to Caucasian and Japanese volunteers.
Methods: In study 1, with a single-blind, parallel-group design, young Japanese and Caucasian male volunteers were randomised to receive four single escalating oral doses of ximelagatran (12, 24, 36 and 60mg on separate days; n = 27 per ethnic group) or placebo (n = 6 per ethnic group). In study 2, with an open-label design, elderly Japanese male volunteers (n = 12) received three single escalating oral doses of ximelagatran (12, 24 and 36mg on separate days).
Results: Regardless of the ethnicity or age of the volunteers, ximelagatran given in single oral doses was rapidly absorbed and bioconverted to melagatran, and the melagatran area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) increased in proportion with the ximelagatran dose, with only small deviations from absolute linearity. Higher melagatran AUC and C(max) were observed in young Japanese volunteers compared with young Caucasian volunteers, and in elderly Japanese volunteers compared with young Japanese volunteers. These results appear to be attributed to weight- and age-related decreases in renal elimination of melagatran rather than to absorption of ximelagatran and formation of melagatran. The pattern of metabolites in plasma and urine was comparable between young Japanese and Caucasian volunteers, and between young and elderly Japanese volunteers. The melagatran plasma concentration-activated partial thromboplastin time (aPTT, an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin) relationship did not differ significantly between young Japanese and Caucasian volunteers or between young and elderly Japanese volunteers.
Conclusions: Ethnicity does not affect the absorption of ximelagatran or the formation of melagatran or the melagatran plasma concentration-aPTT relationship. The elimination of melagatran is correlated with renal function.