ximelagatran and Liver-Diseases

The oral direct thrombin inhibitor ximelagatran is a new class of anticoagulant currently in clinical development for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form melagatran.. To investigate the influence of mild-to-moderate hepatic impairment on the pharmacokinetic and pharmacodynamic properties of ximelagatran.. Nonblinded, nonrandomised study.. Twelve volunteers with mild-to-moderate hepatic impairment (classified as Child-Pugh A or B) and 12 age-, weight-, and sex-matched control volunteers with normal hepatic function.. Volunteers received a single oral dose of ximelagatran 24mg. Plasma and urine samples were collected for pharmacokinetic and pharmacodynamic analyses.. The absorption and bioconversion of ximelagatran to melagatran were rapid in both groups. The maximum plasma concentration of melagatran (Cmax) was achieved 2-3 hours after administration; the mean elimination half-life (t1/2z) was 3.6 hours for hepatically impaired volunteers and 3.1 hours for the control volunteers. The area under the plasma concentration-time curve (AUC) and Cmax of melagatran in volunteers with hepatic impairment were 11 and 25% lower than in control volunteers, respectively. However, after correcting for the higher renal function (i.e. higher calculated creatinine clearance) in the hepatically impaired volunteers, the ratio of melagatran AUC for hepatically impaired/control volunteers was 0.98 (90% CI 0.80, 1.22), suggesting that mild-to-moderate hepatic impairment had no influence on the pharmacokinetics of ximelagatran. Melagatran was the predominant compound in urine, accounting for 13-14% of the ximelagatran dose. Renal clearance of melagatran was 13% higher in hepatically impaired than in control volunteers. There were no significant differences between the two groups in the concentration-response relationship between plasma melagatran concentration and activated partial thromboplastin time (APTT). Baseline prothrombin time (PT) was slightly longer in the hepatically impaired patients than in the control volunteers, probably reflecting a slight decrease in the activity of coagulation factors. However, when concentrations of melagatran were at their peak, the increase in PT from baseline values was the same in both groups. Capillary bleeding time was measured in the hepatically impaired patients only, and was not increased by ximelagatran. Ximelagatran was well tolerated in both groups.. There were no differences in the pharmacokinetic or pharmacodynamic properties of melagatran following oral administration of ximelagatran between the hepatically impaired and control volunteers. These findings suggest that dose adjustment for patients with mild-to-moderate impairment of hepatic function is not necessary.

Topics: Administration, Oral; Adult; Aged; Amidines; Anticoagulants; Area Under Curve; Azetidines; Benzylamines; Glycine; Half-Life; Humans; Liver Diseases; Metabolic Clearance Rate; Middle Aged; Partial Thromboplastin Time; Prodrugs; Prothrombin Time; Thrombin

Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting.. We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants).. RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring.. While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

Topics: Age Factors; Alanine Transaminase; Alcohol Drinking; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Liver; Liver Diseases; Liver Function Tests; Middle Aged; Risk Factors; Time Factors