Ximelagatran

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 426 Experts worldwide ranked by ideXlab platform

David Gustafsson - One of the best experts on this subject based on the ideXlab platform.

  • oral direct thrombin inhibitors in clinical development
    Journal of Internal Medicine, 2003
    Co-Authors: David Gustafsson
    Abstract:

    Thrombin has long been a target for development of oral anticoagulants but it has been difficult to find synthetic inhibitors with a desirable combination of pharmacodynamic and pharmacokinetic properties. However, there are now two oral direct thrombin inhibitors (DTIs) in clinical development, Ximelagatran (ExantaTM) and BIBR 1048. Both are prodrugs with two protecting groups that are eliminated after absorption from the gastrointestinal tract. Their main active substances, melagatran and BIBR 953, are both potent and selective DTIs. In experimental models of thrombosis, melagatran has been shown to have a shallower dose-response curve than warfarin and, therefore, a better separation between efficacy and bleeding. Oral bioavailability, measured as the plasma concentration of the active metabolite, seems to be higher for Ximelagatran (20%) than for BIBR 1048 (estimated to 5%). BIBR 953 has a longer half-life (about 12 h) than does melagatran (3-5 h) after oral administration of BIBR 1048 and Ximelagatran, respectively. Both melagatran and BIBR 953 are mainly eliminated via the renal route. The variability of the plasma concentration of melagatran after oral administration of Ximelagatran is low. There are no clinically relevant interactions with food or cytochrome P450 metabolized drugs and Ximelagatran. In clinical studies, Ximelagatran has been administered in a twice-daily fixed-dose regimen without coagulation monitoring. Results of published clinical studies are encouraging, both with regard to efficacy and bleeding. Major indications in Phase III studies with Ximelagatran are the prevention of venous thromboembolism (VTE) in hip and knee replacement surgery, treatment and long-term secondary prevention of VTE and prevention of stroke in patients with nonvalvular atrial fibrillation. It is anticipated that with a favourable outcome of the Phase III clinical studies new oral DTIs, with the oral fixed-dose regimen without routine coagulation monitoring, will ease the use of today's anticoagulant therapy.

  • the pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor Ximelagatran and its active metabolite melagatran a mini review
    Thrombosis Research, 2003
    Co-Authors: David Gustafsson
    Abstract:

    Abstract Ximelagatran (Exanta™, AstraZeneca) is a novel, oral direct thrombin inhibitor (oral DTI) that is rapidly converted to melagatran, its active form, following absorption. Melagatran has been shown to be a potent, rapidly binding, competitive inhibitor of human α-thrombin that inhibits both thrombin activity and generation. Melagatran also effectively inhibits both free and clot-bound thrombin. Melagatran has a wide therapeutic interval that enables it to be administered safely across a wide range of doses with no increased risk of bleeding, in contrast with warfarin whose narrow therapeutic window necessitates monitoring of its pharmacodynamic effect. Although melagatran has all the pharmacodynamic properties required of a new antithrombotic agent, low oral bioavailability that is even further reduced by the concomitant intake of food precludes its development as an oral agent. It was this that propelled the development of its prodrug, Ximelagatran, which is 170 times more lipophilic than melagatran and uncharged at intestinal pH. Ximelagatran is therefore much better than melagatran at penetrating the gastrointestinal barrier and, as a consequence, has sufficient bioavailability (20%) for oral administration. Moreover, its pharmacokinetic properties following oral administration are stable and reproducible, with no food interactions and a low potential for drug–drug interactions. These properties allow Ximelagatran to be administered twice daily according to a fixed dose regimen without coagulation monitoring. As a consequence of its favourable pharmacokinetic and pharmacodynamic properties, Ximelagatran is currently undergoing full-scale clinical development for the prophylaxis and treatment of thromboembolic disorders.

  • pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral Ximelagatran a population model analysis
    Clinical Pharmacokinectics, 2003
    Co-Authors: Ulf G. Eriksson, Lars Frison, Per Olsson Gisleskog, Ulrika Wahlby, Bengt Hamren, David Gustafsson, Jaap W Mandema, Mats O Karlsson, Bengt I Eriksson
    Abstract:

    Objective: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. 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. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated Creatinine clearance was examined.

  • absorption distribution metabolism and excretion of Ximelagatran an oral direct thrombin inhibitor in rats dogs and humans
    Drug Metabolism and Disposition, 2003
    Co-Authors: Ulf G. Eriksson, Ulf Bredberg, Kurtjurgen Hoffmann, Gunnar Fager, Anneli Thuresson, Margareth Gabrielsson, Hans Ericsson, Martin Ahnoff, Kristina Gislen, David Gustafsson
    Abstract:

    The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, Ximelagatran, and its active form, melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. Ximelagatran was rapidly absorbed and metabolized following oral administration, with melagatran as the predominant compound in plasma. Two intermediates (ethyl-melagatran and OH-melagatran) that were subsequently metabolized to melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. Ximelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of Ximelagatran. 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. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of melagatran following oral administration of Ximelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of Ximelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of Ximelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of melagatran.

  • effects of Ximelagatran an oral direct thrombin inhibitor r hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects
    Journal of the American College of Cardiology, 2003
    Co-Authors: Troy C Sarich, Ulf G. Eriksson, Michael Wolzt, Christer Mattsson, Gunnar Fager, Magnus Andersson, Maria Wollbratt, Alice Schmidt, Susanne Elg, David Gustafsson
    Abstract:

    Abstract Objectives The effects of Ximelagatran, an oral direct thrombin inhibitor (DTI), recombinant hirudin (r-hirudin) and enoxaparin on thrombin generation and platelet activation were studied in humans. Background Recombinant hirudin (parenteral DTI) and enoxaparin (low molecular weight heparin) have been demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism. The shed blood model allows for the study of thrombin generation and platelet activation in humans in vivo. Methods This was an open-label, parallel-group study involving 120 healthy male volunteers randomized to receive one of three oral doses of Ximelagatran (15, 30 or 60 mg), r-hirudin (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically effective in acute coronary syndromes, or to serve as a control. Thrombin generation (prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex [TAT]) and platelet activation (β-thromboglobulin [β-TG]) biomarkers were studied using a shed blood model involving blood collection from skin incisions made using standardized bleeding time devices. Results Oral Ximelagatran, intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p 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. The inhibition of thrombin generation by 60 mg Ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes.

Bengt I Eriksson - One of the best experts on this subject based on the ideXlab platform.

  • safety assessment of new antithrombotic agents lessons from the extend study on Ximelagatran
    Thrombosis Research, 2009
    Co-Authors: Giancarlo Agnelli, Bengt I Eriksson, Alexander T Cohen, David Bergqvist, Ola E Dahl, M R Lassen, Patrick Mouret, Nadia Rosencher, M Andersson, Anders Bylock
    Abstract:

    Abstract Background Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. Objectives and Methods The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of Ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. Results Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of Ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 Ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to > 2× upper limit of normal: 31 treated with enoxaparin, 27 with Ximelagatran. Three Ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven Ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of Ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. Conclusions Prolonged administration of Ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with Ximelagatran should be considered when designing studies with new antithrombotic agents.

  • postoperative melagatran Ximelagatran for the prevention of venous thromboembolism following major elective orthopaedic surgery effects of timing of first dose and risk factors for thromboembolism and bleeding complications on efficacy and safety
    Clinical Drug Investigation, 2005
    Co-Authors: Ola E Dahl, Bengt I Eriksson, Giancarlo Agnelli, Alexander T Cohen, Patrick Mouret, Nadia Rosencher, Anders Bylock, Seva Panfilov, Magnus Andersson
    Abstract:

    Objectives: To examine the influence of timing of postoperative initiation of subcutaneous melagatran followed by oral Ximelagatran, and of risk factors for venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and bleeding complications, on the efficacy and safety of this regimen, compared with preoperative enoxaparin sodium, following total hip replacement (THR) or total knee replacement (TKR) surgery. Design: Statistical analyses of efficacy and safety in subgroups of the METHRO III intention-to-treat population. Main outcome measures: Main efficacy outcome measures were major VTE (proximal DVT, PE or VTE-related death) and total VTE (distal or proximal DVT, fatal or non-fatal PE). The main safety outcome measures were blood transfusion, severe bleeding events, blood loss, bleeding-related adverse events and need for reoperation. Results: In the combined THR and TKR population, melagatran initiated 4–<8 hours postoperatively was non-inferior to enoxaparin sodium with respect to the risks of total VTE (absolute risk reduction [ARR] 0; 95% confidence interval [CI] ∼-4.4, 4.4) and major VTE (ARR −0.63; 95% CI −2.94, 1.67). The rate of major VTE was unaffected by the different risk factors. In the combined THR and TKR population, blood transfusion requirements were lower with melagatran/ximela-gatran than enoxaparin sodium (odds ratio 0.83; 95% CI 0.71, 0.96; p = 0.016). Conclusions: Melagatran/Ximelagatran initiated 4–<8 hours postoperatively provided a comparable level of protection against total and major VTE to preoperative enoxaparin sodium. Major VTE rates and safety were consistent across different patient subgroups. Subcutaneous melagatran followed by fixed-dose oral Ximelagatran offers an alternative to the standard European low molecular-weight heparin regimen in a wide range of patients.

  • significantly lower need for blood transfusions associated with postoperatively initiated subcutaneous melagatran oral Ximelagatran compared with enoxaparin
    Thrombosis and Haemostasis, 2004
    Co-Authors: Bengt I Eriksson, Giancarlo Agnelli, Ola E Dahl, Patrick Mouret, Nadia Rosencher, Seva Panfilov
    Abstract:

    Significantly lower need for blood transfusions associated with postoperatively initiated subcutaneous melagatran/oral Ximelagatran compared with enoxaparin -

  • o1065 Ximelagatran and its subcutaneous form melagatran vs enoxaparin as thromboprophylaxis in total hip or total knee replacement
    Orthopaedic Proceedings, 2004
    Co-Authors: Bengt I Eriksson, Giancarlo Agnelli, Ola E Dahl, M R Lassen, Patrick Mouret, Nadia Rosencher
    Abstract:

    Aims: To investigate the efficacy and safety of a new dosage regimen of the oral direct thrombin inhibitor Ximelagatran, and its subcutaneous (sc) form melagatran, started in close proximity to surgery. Methods: In a randomised, double-blind, parallel-group study, duration 8–11 days, patients undergoing total hip or knee replacement (THR, n= 1856; TKR, n= 908) received either sc melagatran 2 mg immediately before surgery followed by sc 3 mg in the evening after surgery, and then by oral Ximelagatran 24 mg bid as a fixed dose (the Ximelagatran group), or sc enoxaparin 40 mg od, started the evening before surgery. Bilateral venography was performed on the final day of treatment. Results: The rate of proximal deep vein thrombosis plus pulmonary embolism was 2.3% in the Ximelagatran group vs. 6.3% in the enoxaparin group (p Conclusion: Pre-operatively initiated sc melagatran followed by oral Ximelagatran was superior in efficacy to enoxaparin in preventing VTE in patients undergoing THR or TKR.

  • prevention of venous thromboembolism following orthopaedic surgery clinical potential of direct thrombin inhibitors
    Drugs, 2004
    Co-Authors: Bengt I Eriksson, Ola E Dahl
    Abstract:

    Patients undergoing total hip or total knee replacement are at high risk of venous thromboembolism (VTE), and are therefore considered to be populations well suited for the evaluation and dose optimisation of new anticoagulants. Deep vein thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic events. There is increasing evidence that anticoagulant treatment for the prevention of VTE should be extended from 1 to at least 4 weeks after surgery. Anticoagulation with vitamin K antagonists (such as warfarin), low molecular weight heparin or unfractionated heparin effectively lowers the risk of VTE, but these anticoagulants have limitations such as the need for coagulation monitoring and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing prophylaxis out of hospital because of the requirement for parenteral administration, and risk of heparin-induced thrombocytopenia. The development of new anticoagulants has been pursued with the aim of finding more effective, safer and/or more convenient therapies. Thrombin is a central regulator in the coagulation and inflammation process and several direct thrombin inhibitors (DTIs) with distinct pharmacological profiles, as well as pharmacological differences from the conventional anticoagulants, are currently in clinical use for certain indications or are under development. Clinical experience with parenterally administered DTIs has accumulated since the mid 1990s, although only desirudin (a recombinant hirudin) is currently approved for use in patients undergoing orthopaedic surgery. Two oral DTIs, Ximelagatran and dabigatran etexilate, are in clinical development. Dabigatran etexilate has recently been evaluated in phase II clinical trials in patients undergoing total hip replacement. Several large phase III trials have now demonstrated the efficacy and safety of Ximelagatran in the prevention of VTE following total hip or knee replacement. Ximelagatran can be used with an oral fixed dose without the need for coagulation monitoring or dose adjustment. Hence, it offers significant potential to facilitate the management of anticoagulation in or out of hospital.

Lars Frison - One of the best experts on this subject based on the ideXlab platform.

Charles W Francis - One of the best experts on this subject based on the ideXlab platform.

  • oral direct thrombin inhibitor Ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty
    Journal of Bone and Joint Surgery American Volume, 2005
    Co-Authors: Clifford W Colwell, Scott D Berkowitz, Jay R Lieberman, Jeffrey S Ginsberg, Guy Paiement, Jennifer Mcelhattan, Anne W Roth, Charles W Francis
    Abstract:

    Background: Warfarin, which requires coagulation monitoring, is associated with relatively high rates of thromboembolism despite providing adequate prophylaxis. This study compared an oral direct thrombin inhibitor, Ximelagatran, with warfarin in order to evaluate the safety and efficacy of the medication for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. Methods: Following surgery, patients were randomly assigned to fixed-dose oral Ximelagatran (36 mg twice daily) or warfarin (target international normalized ratio, 2.5), both administered for seven to twelve days in a double-blind, double-dummy design. Warfarin was initiated on the evening of the day of surgery, and Ximelagatran, on the morning after surgery. The primary efficacy end point was the incidence of asymptomatic deep-vein thrombosis determined by bilateral venography, objectively confirmed symptomatic deep-vein thrombosis or pulmonary embolism, and death from all causes during treatment. Results: Adequate venograms or confirmed symptomatic events (efficacy population) were obtained for 1949 patients. Venous thromboembolism and death from all causes occurred in 22.5% (221) of 982 Ximelagatran-treated patients and in 31.9% (308) of 967 warfarin-treated patients (p < 0.001). Proximal deep-vein thrombosis and pulmonary embolism were observed in 3.1% (thirty) and 0.2%, respectively, of the patients in the Ximelagatran group and in 3.4% (thirty-three) and 0.4%, respectively, of the patients in the warfarin group. The six deaths from all causes included 0.3% (four) of the Ximelagatran-treated patients and 0.2% (two) of the warfarin-treated patients. Major bleeding was noted in 1% (twelve) of the Ximelagatran-treated patients and in 0.4% (five) of the warfarin-treated patients (p = 0.09). Conclusions: Oral Ximelagatran (36 mg twice daily), administered without coagulation monitoring or dose adjustment and started the day after total knee arthroplasty, demonstrates superior efficacy compared with warfarin prophylaxis, with no wound complications and no significant difference with respect to bleeding events, although the rate of major bleeding events was greater with Ximelagatran than with warfarin. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

  • Ximelagatran vs low molecular weight heparin and warfarin for the treatment of deep vein thrombosis a randomized trial
    JAMA, 2005
    Co-Authors: Jeannoel Fiessinger, Per Nystrom, Charles W Francis, Scott D Berkowitz, Torbjorn Lundstrom, Henry Eriksson, Menno V Huisman, Bruce L Davidson, Henri Bounameaux, Mona Thorsen
    Abstract:

    ContextXimelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism.ObjectiveTo compare the efficacy and safety of Ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.Design, Setting, and PatientsRandomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.InterventionsPatients were randomized to receive 6 months of treatment with either oral Ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.Main Outcome MeasuresRecurrent venous thromboembolism, bleeding, and mortality.ResultsVenous thromboembolism recurred in 26 of the 1240 patients assigned to receive Ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between Ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], –1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, −1.0%; 95% CI, –2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, –1.1%; 95% CI, –2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving Ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with Ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).ConclusionsOral Ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of Ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.

  • comparison of Ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement
    The New England Journal of Medicine, 2003
    Co-Authors: Charles W Francis, Gary Peters, Scott D Berkowitz, Jay R Lieberman, Jeffrey S Ginsberg, Guy Paiement, Jennifer Mcelhattan, Anne W Roth, Clifford W Colwell
    Abstract:

    Background In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of Ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of Ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of Ximelagatran is superior to warfarin. Methods This randomized, double-blind trial compared a regimen of 7 to 12 days of oral Ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. The composite end point of venous thromboembolism and death from all causes and the incidence of bleeding were the primary outcome measures. Results Among the 1851 patients in the efficacy analysis, oral Ximelagatran at a dose of 36 mg twice daily was superior to warfarin with respect to the primary composite end point of venous thrombo...

  • direct thrombin inhibitors
    Seminars in Hematology, 2002
    Co-Authors: Karen L Kaplan, Charles W Francis
    Abstract:

    Abstract Direct thrombin inhibitors interact with thrombin and block its catalytic activity on a wide range of substrates. Their action is in contrast to heparin and its derivatives, which inhibit thrombin and other coagulation serine proteases via antithrombin, and to the warfarin-type drugs that interfere with synthesis of the precursors of the coagulation serine proteases. There are three direct thrombin inhibitors approved for clinical use at present (lepirudin, bivalirudin, argatroban) and another in advanced clinical testing (melagatran/Ximelagatran). The chemical structure, kinetics of thrombin inhibition, pharmacokinetics, and clinical use of each of these agents are discussed. Semin Hematol 39:187-196. Copyright 2002, Elsevier Science (USA). All rights reserved.

Ulf Eriksson - One of the best experts on this subject based on the ideXlab platform.

  • effect on perfusion chamber thrombus size in patients with atrial fibrillation during anticoagulant treatment with oral direct thrombin inhibitors azd0837 or Ximelagatran or with vitamin k antagonists
    Thrombosis Research, 2012
    Co-Authors: Michael Wolzt, Ulf Eriksson, Margareta Elg, Kajsmarie Schutzer, Ghazaleh Gouya, Nicolai Leuchten, Stylianos Kapiotis, Sofia Zetterstrand, Malin Holmberg, Karin Wahlander
    Abstract:

    Abstract Introduction AZD0837 and Ximelagatran are oral direct thrombin inhibitors that are rapidly absorbed and bioconverted to their active forms, AR-H067637 and melagatran, respectively. This study investigated the antithrombotic effect of AZD0837, compared to Ximelagatran and the vitamin K antagonist (VKA) phenprocoumon (Marcoumar®), in a disease model of thrombosis in patients with non-valvular atrial fibrillation (NVAF). Methods Open, parallel-group studies were performed in NVAF patients treated with VKA, which was stopped aiming for an international normalized ratio (INR) of ≤ 2 before randomization. Study I: 38 patients randomized to AZD0837 (150, 250 or 350 mg) or Ximelagatran 36 mg twice daily for 10–14 days. Study II: 27 patients randomized to AZD0837 250 mg twice daily or VKA titrated to an INR of 2–3 for 10–14 days. A control group of 20 healthy elderly subjects without NVAF or anticoagulant treatment was also studied. Size of thrombus formed on pig aorta strips was measured after a 5-minute perfusion at low shear rate with blood from the patient/control subject. Results Thrombus formation was inhibited by AZD0837 and Ximelagatran. Relative to untreated patients, a 50% reduction of thrombus size was estimated at plasma concentrations of 0.6 and 0.2 μmol/L for AR-H067637 and melagatran, respectively. For patients receiving VKA treatment, the thrombus size was about 15% lower compared with healthy elderly controls. Conclusions Effects of AZD0837 and Ximelagatran on thrombus formation were similar or greater than for VKA therapy and correlated with plasma concentrations of their active forms.

  • comparable pharmacokinetics and pharmacodynamics of melagatran in japanese and caucasian volunteers after oral administration of the direct thrombin inhibitor Ximelagatran
    Clinical Pharmacokinectics, 2006
    Co-Authors: Linda Wernevik, Anders Bylock, Magnus Andersson, Per Nystrom, Gillis Johnsson, Takashi Nakanishi, Ulf Eriksson
    Abstract:

    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. 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). 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 (Cmax) increased in proportion with the Ximelagatran dose, with only small deviations from absolute linearity. Higher melagatran AUC and Cmax 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. 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.

  • population pharmacokinetics of melagatran the active form of the oral direct thrombin inhibitor Ximelagatran in atrial fibrillation patients receiving long term anticoagulation therapy
    Clinical Pharmacokinectics, 2006
    Co-Authors: Sofie Baathe, Bengt Hamren, Mats O Karlsson, Maria Wollbratt, Margaretha Grind, Ulf Eriksson
    Abstract:

    Background Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, Ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran.

  • low potential for interactions between melagatran Ximelagatran and other drugs food or alcohol
    Seminars in Vascular Medicine, 2005
    Co-Authors: Michael Wolzt, Troy C Sarich, Ulf Eriksson
    Abstract:

    Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, Ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of Ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral Ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with Ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral Ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when Ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.

  • effect of erythromycin on the pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor Ximelagatran and its active form melagatran
    Clinical Pharmacology & Therapeutics, 2004
    Co-Authors: Hassan Dorani, Troy C Sarich, Lis Ohlsson, Kajsmarie Schutzer, Ulrika Wall, Ulf Eriksson
    Abstract:

    Background Ximelagatran (Exanta™, AstraZeneca), an oral direct thrombin inhibitor for the prevention and treatment of thromboembolic disorders, is rapidly absorbed and bioconverted to its active form melagatran. The metabolism of Ximelagatran is independent of CYP450 enzymes and hence it has a low potential for drug interactions. This study evaluated the effect of erythromycin on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran. Methods: An open, sequential, single-centre study in healthy volunteers (n=16; mean age 24 years, range 20–32 years) with Ximelagatran 36mg on Day 1, then erythromycin 500mg TID on Days 2–5 followed by Ximelagatran 36 mg plus erythromycin on Day 6. Results: For melagatran, AUC and Cmax geometric mean ratios for combined therapy (Day 6) relative to monotherapy (Day 1) were 1.82 (90% CI, 1.64–2.01) and 1.74 (90% CI, 1.52–2.00), respectively, (n=15), falling outside of the predefined bounds for no interaction. Geometric mean ratios for tmax and t1/2 of melagatran were 1.14 and 0.93, respectively. The erythromycin-associated elevation in plasma melagatran concentrations increased the peak activated partial thromboplastin time (aPTT) prolongation from 41s to 44s. Ximelagatran was well tolerated alone, and in combination with erythromycin. Conclusions: This study showed evidence of a pharmacokinetic interaction between Ximelagatran and erythromycin with respect to melagatran PK, which is being investigated, but only a small effect on aPTT. Clinical Pharmacology & Therapeutics (2004) 75, P78–P78; doi: 10.1016/j.clpt.2003.11.295

Related terms

Ximelagatran - 15 days free trial to Access Experts & Abstracts