No Influence of Ethnic Origin on the Pharmacokinetics and Pharmacodynamics of Melagatran Following Oral Administration of Ximelagatran, a Novel Oral Direct Thrombin Inhibitor, to Healthy Male Volunteers

Abstract

To determine the influence of ethnic origin on the pharmacokinetic and pharmacodynamic properties of melagatran after oral administration of ximelagatran, a novel oral direct thrombin inhibitor. This was an open-label, non-randomised study with a single study session. Thirty-six young healthy male subjects living in France were divided equally according to their ethnic origin (African, Asian and Caucasian). All subjects received a single 50mg oral dose of ximelagatran in solution. Blood and urine samples for pharmacokinetic evaluation were collected up to 12 and 24 hours after administration, respectively. Blood samples were also collected to determine the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin, up to 24 hours after administration. The absorption of ximelagatran, and its bioconversion to melagatran, was rapid in all three ethnic groups. The metabolite pattern in plasma and urine was similar in all groups, with melagatran being the dominant compound. For ximelagatran, the mean area under the plasma concentration-time curve (AUC) was similar in the three groups, suggesting that there was no difference in the extent to which ximelagatran was absorbed. Melagatran AUC was higher in the Asian subjects, with a mean Asian/Caucasian ratio (95% CI) of 1.23 (1.04, 1.45). This was presumably because of their lower bodyweight, which is correlated to lower renal function. Following normalisation for bodyweight, there were no statistically significant differences between the three ethnic groups. This finding suggests that renal elimination was lower for Asian subjects, whereas there were no differences in the conversion of ximelagatran to melagatran. The interindividual variability of melagatran AUC was low (coefficient of variation 19-26%), and the mean bioavailability of melagatran, estimated using a mean value for melagatran clearance obtained from Caucasian subjects in a previous study, was approximately 20% in all groups (range of mean values 19-23%). APTT increased nonlinearly with increasing melagatran plasma concentration, and no difference in the concentration-response relationship was observed between the groups. After oral administration of ximelagatran, the pharmacokinetic and pharmacodynamic properties of melagatran are independent of ethnic origin. The elimination of melagatran is correlated with renal function.