Disease relevance of Exanta

• Large phase 3 trials evaluating ximelagatran for the secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with atrial fibrillation have been completed [1].
• Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism [2].
• Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively [3].
• One ischemic stroke (nonfatal) and one transient ischemic attack (TIA) occurred in the ximelagatran group [4].
• Risk factors for bleeding with ximelagatran were as follows (hazard ratios and 95% CIs in parentheses): diabetes mellitus (1.81; 1.19-2.77; P = .006), previous stroke or transient ischemic attack (1.78; 1.16-2.73; P = .008), age 75 years or greater (1.70; 1.33-2.18; P<.001), and aspirin use (1.68; 1.08-2.59; P = .02) [5].

Psychiatry related information on Exanta

• The primary event rate by intention to treat was 2.3% per year with warfarin and 1.6% per year with ximelagatran (absolute risk reduction 0.7% [95% CI -0.1 to 1.4], p=0.10; relative risk reduction 29% [95% CI -6.5 to 52]) [6].

High impact information on Exanta

• Annual incidence of major bleeding was 2.01% with ximelagatran and 2.68% with warfarin (relative risk reduction, 25.1%; 95% CI, 3.2-42.1; P = .03) [5].
• Elevation of serum alanine aminotransferase levels above 3x the upper limit of normal occurred in approximately 6% of ximelagatran-treated patients but typically returned toward pretreatment levels without associated symptoms [7].
• Ximelagatran is a novel, oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions [4].
• Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects [2].
• CONCLUSIONS: Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model [2].

Chemical compound and disease context of Exanta

• CONCLUSIONS: Treatment with ximelagatran, 36 mg twice daily, is associated with a lower risk of bleeding than warfarin in patients with nonvalvular atrial fibrillation [5].
• Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3) [3].
• CONCLUSIONS: The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration [8].
• Oral ximelagatran plus ASA has a greater antithrombotic effect in this human ex vivo thrombosis model and a less pronounced prolongation of bleeding time than clopidogrel plus ASA [9].
• INTERPRETATION: Oral direct thrombin inhibition with ximelagatran and acetylsalicylic acid is more effective than acetylsalicylic acid alone in preventing major cardiovascular events during 6 months of treatment in patients who have had a recent myocardial infarction [10].

Biological context of Exanta

• Capillary bleeding time was measured in the hepatically impaired patients only, and was not increased by ximelagatran [11].
• The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23% [12].
• The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism [12].
• 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 [13].
• CONCLUSIONS: 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 [14].

Anatomical context of Exanta

• Melagatran was the major compound in urine and feces after administration of ximelagatran [15].
• In summary, ximelagatran and N-hydroxy-melagatran are easily reduced by several enzyme systems located in microsomes and mitochondria of different organs [16].
• Appreciable quantities of ethyl-melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract, as demonstrated when ximelagatran was incubated with feces homogenate [15].
• The protocols and results of some of these studies--and a study that investigates the use of ximelagatran in combination with aspirin for the management of acute coronary artery disease--are described in this paper [17].
• As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran [18].

Associations of Exanta with other chemical compounds

• Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran [19].
• Moreover, there were no statistically significant differences in the pharmacokinetics of melagatran when ximelagatran was administered alone or in combination with diclofenac, diazepam or nifedipine [20].
• Ximelagatran plus ASA reduced TTA more than clopidogrel plus ASA under LSR after 2 hours (36 mg, P=0.0011; 72 mg, P<0.0001) and 5 hours (72 mg, P=0.0057), and under HSR after 2 and 5 hours (72 mg, P<0.05) [9].
• CONCLUSION: As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes [20].
• The interaction potential of digoxin and ximelagatran, an oral direct thrombin inhibitor being developed for the prevention and treatment of thromboembolic disease, was investigated in this randomized, double-blind, 2-way crossover study [21].

Gene context of Exanta

• Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4 [20].
• Three other new agents-activated protein C (APC), tissue factor pathway inhibitor (TFPI), and the oral DTI ximelagatran (Exanta, AstraZeneca)-have been evaluated in Phase III studies [22].
• Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran [20].
• Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASA alone [9].
• Alcohol did not alter the melagatran-induced prolongation of the activated partial thromboplastin time or the good tolerability/safety profile of ximelagatran [23].

Analytical, diagnostic and therapeutic context of Exanta

• CONCLUSION: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement [3].
• METHODS AND RESULTS: SPORTIF III (open label, n=3410) and V (double-blind, n=3922) included 2257 women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0-3.0] or ximelagatran (36 mg twice daily) [24].
• In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively [25].
• METHODS: All subjects received a 2mg intravenous infusion of melagatran over 10 minutes followed, in randomised sequence, by a 20 mg immediate-release tablet of ximelagatran with breakfast, a 20 mg immediate-release tablet of ximelagatran while fasting, and a 7.5 mg subcutaneous injection of ximelagatran [14].
• In addition, the USA clinical trial programme included three other trials that investigated ximelagatran in orthopaedic surgery; two of these studies focused on prevention of venous thromboembolism after total knee replacement, and one study investigated prevention of venous thromboembolism after total hip replacement [26].

References