ximelagatran and melagatran

The direct thrombin inhibitor, ximelagatran, and its active form, melagatran (X/M), have been compared against conventional anticoagulant therapy (CAT) in many clinical settings. Their risk-benefit profile drove large debate until withdrawal by the manufacturer. A systematic review of all published randomized trials has been performed and a meta-analysis of randomised controlled trial (RCT) of X/M versus CAT. Major medical databases were searched for RCTs. Major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, pulmonary embolism), major bleeds (MB), minor bleeds and the rate of hepatotoxicity (HT) were compared. In terms of efficacy, X/M was at least as effective as, or even superior to, CAT. In terms of safety, the overall risk of MAE, MB, minor bleeds and HT was not significantly different for X/M compared with CAT. According to individual clinical settings, X/M was associated with a lower risk of MB but a prohibitive higher risk of HT in those clinical settings requiring prolonged treatment.

Topics: Animals; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Evidence-Based Medicine; Humans; Risk Assessment; Thrombin

The coagulation cascade, and particularly thrombin, plays a very important role in arterial and venous thrombosis. Thereby, it is clear that thrombin inactivation is an optimal strategy for thrombotic disease prevention and treatment. The direct thrombin inhibitors are a new class of anticoagulant drugs directly binding thrombin and blocking its interaction with fibrinogen. The group of direct thrombin inhibitors includes recombinant hirudin (lepirudin and desirudin), bivalirudin, melagatran and its oral precursor, ximelagatran, argotraban and dabigatran. These drugs have several advantages compared to other anticoagulant drugs, and the particular pharmacokinetic properties of some of them could be very important for future management of thromboembolic prophylaxis. The efficacy and safety of these new drugs are evaluated in several clinical trials; however today only few clinical indications are available for the majority of them.

Topics: Anticoagulants; Antithrombins; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Therapy, Combination; Fibrinolytic Agents; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thromboembolism; Treatment Outcome

Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Heart Diseases; Hemostasis; Humans; Molecular Structure; Orthopedic Procedures; Patient Compliance; Patient Satisfaction; Platelet Aggregation; Prodrugs; Stroke; Syndrome; Thrombin; Thromboembolism; Treatment Outcome; Venous Thrombosis

Ximelagatran is an oral direct thrombin inhibitor (DTI), the active form of which is melagatran. Approximately 20% of an oral ximelagatran dose becomes bioavailable as melagatran, which binds noncovalently and reversibly to both fibrin-bound and freely circulating thrombin. Oral ximelagatran dosing not only inhibits thrombin activity rapidly, competitively, and potently, but also delays and suppresses thrombin generation. In humans, oral ximelagatran exhibits anticoagulant, antiplatelet, and profibrinolytic effects, with only minor prolongation of the capillary bleeding time. Oral ximelagatran exhibits a stable and predictable pharmacokinetic profile during repeated dosing, with low intra- and inter-individual variation, and a low potential for interaction with other medications. It is excreted primarily as melagatran via the kidney, without unexpected bioaccumulation. Dosing requirements do not vary with age, gender, ethnicity, obesity, or food or alcohol intake. Clinical trials (total n>30,000) have evaluated oral ximelagatran in four indications: the prevention of venous thromboembolism (VTE, comprising deep venous thrombosis with or without and pulmonary embolism) after elective hip- or knee-replacement surgery (with approval granted by France, as the Reference Member State for the European Union); treatment and long-term secondary prevention of VTE; the prevention of stroke and other systemic embolic events associated with nonvalvular atrial fibrillation; and the prevention of cardiovascular events after an acute myocardial infarction. The results of these trials suggest that the benefit-risk profile of oral ximelagatran therapy, administered at a fixed-dose without coagulation monitoring, compares favorably with that of currently approved standard therapy.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Glycine; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Thrombin; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Fibrinolytic Agents; Glycine; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Orthopedics; Random Allocation; Regression Analysis; Risk; Risk Factors; Thrombin; Thromboembolism

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Oral anticoagulant therapy with vitamin K antagonists (VKAs) such as warfarin has proven benefits in the treatment and prevention of thromboembolic disorders but has important limitations that result in substantial underuse. In particular, the VKAs have variable and unpredictable pharmacokinetics and pharmacodynamics and a narrow separation between antithrombotic and hemorrhagic effects that necessitates careful dose adjustment based on frequent coagulation monitoring. In contrast, the oral direct thrombin inhibitor ximelagatran has a predictable and reproducible pharmacokinetic/pharmacodynamic profile that allows treatment using fixed-dose regimens without coagulation monitoring. The bioavailability of melagatran, the active form of ximelagatran, after oral administration of ximelagatran is approximately 20% with low inter- and intra-individual variability. Peak plasma melagatran concentrations are reached approximately 2 hours after oral dosing of ximelagatran to healthy volunteers, and melagatran is eliminated with a half-life of approximately 3 hours with clearance predominantly by renal excretion. Hence, a higher melagatran exposure is seen in patients with renal failure; ximelagatran is currently not recommended for patients with severe renal impairment (creatinine clearance of <30 mL/min) as these patients were not included in the clinical trial program. Exposure to melagatran increases linearly with the ximelagatran dose. The pharmacokinetic/pharmacodynamic profile is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Any differences in melagatran pharmacokinetics associated with these factors are attributable to differences in renal function.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Biological Availability; Glycine; Humans; Thrombin

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.

Topics: Anticoagulants; Azetidines; Benzylamines; Cytochrome P-450 Enzyme System; Drug Interactions; Ethanol; Food; Glycine; Humans

Current antithrombotic agents include anticoagulants (unfractionated and low-molecular-weight heparin, and antivitamin K) and platelet aggregation inhibitors (aspirin, ticlopidine, clopidogrel). Two areas are under particular investigation: specific inhibition, direct or indirect, of factor Xa and factor IIa. Pentasaccharide, an indirect anti-Xa, has proved effective in curing deep-vein thrombosis and more effective than enoxaparin for prophylactic treatment after orthopedic surgery. Administered in a single subcutaneous injection daily, it has no risk of thrombocytopenia; laboratory surveillance is based on anti-Xa activity. Hirudin and melagatran act by direct thrombin inhibition. Unlike hirudin (which requires monitoring of active coagulation time or ecarin clotting time), melagatran requires no laboratory monitoring. It is not associated with an increased risk of hemorrhage. But there is no true antidote at this time. If its efficacy is confirmed, ximelagatran, the orally active prodrug of melagatran, may facilitate the long-term treatment now reserved for antivitamin K. Three antagonists of the tissue factor-factor VIIa complex are also under development: rNAPc2 (Recombinant Nematode Anticoagulant Protein C2), ASIS (Active Site Inhibitor Factor Seven) and recombinant TFPI (Tissue Factor Pathway Inhibitor). Antiplatelet drugs are the reference antithrombotic agents for the prevention and treatment of arterial thrombosis. Aspirin remains in first place (75 to 300 mg/d) but the modest superiority of the thienopyridines (clopidogrel and ticlopidine) is established. Hemogram monitoring is no longer necessary for clopidogrel. Use of aspirin + a thienopyridine after placement of a coronary stent has been validated. Laboratory monitoring of antiplatelet treatments has not been codified.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Azetidines; Benzylamines; Clopidogrel; Fibrinolytic Agents; Glycine; Hirudins; Humans; Injections, Subcutaneous; Platelet Aggregation Inhibitors; Polysaccharides; Prodrugs; Randomized Controlled Trials as Topic; Stents; Thrombosis; Ticlopidine; Time Factors; Venous Thrombosis

Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and its active form, melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement. After oral administration ximelagatran is rapidly bioconverted to melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time. The efficacy of subcutaneous melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials. In a dose-ranging European study, preoperatively initiated subcutaneous melagatran 3 mg twice daily followed by oral ximelagatran 24 mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous melagatran 3 mg administered after surgery followed by ximelagatran 24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the US, four studies showed that postoperatively initiated ximelagatran 24 mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.Ximelagatran alone or after melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients.. Oral ximelagatran alone or in conjunction with subcutaneous melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.

Topics: Anticoagulants; Azetidines; Benzylamines; Drug Interactions; Drug Therapy, Combination; Enoxaparin; Glycine; Humans; Orthopedic Procedures; Randomized Controlled Trials as Topic; Thrombin; Thromboembolism; Venous Thrombosis; Warfarin

Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that inhibits the final step in the coagulation process - namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Recently completed large clinical trials have evaluated the efficacy and safety of ximelagatran compared to standard anticoagulation therapy with warfarin and heparins in several thrombotic disorders including the treatment and prevention of venous thromboembolism following major orthopaedic surgery; stroke prevention in atrial fibrillation; and after acute myocardial infarction. This article reviews these recent clinical trials and explores the therapeutic potential of ximelagatran to become the oral anticoagulant of first choice in medicine.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Artery Disease; Drug Therapy, Combination; Glycine; Humans; Prodrugs; Stroke; Thrombin; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Fondaparinux; Glycine; Heparin; Hirudin Therapy; Humans; Pipecolic Acids; Polysaccharides; Prodrugs; Sulfonamides; Thrombin; Venous Thrombosis

Melagatran is a synthetic, small-peptide direct thrombin inhibitor with anticoagulant activity. Ximelagatran, an oral prodrug, undergoes rapid enzymatic conversion to melagatran. Melagatran has rapid onset of action, fixed twice-daily dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring drug levels or dose adjustment. There is no specific antidote, but the drug has a short plasma elimination half-life (about 4 hours). In clinical studies, melagatran/ximelagatran is not inferior to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, to heparin-warfarin for acute treatment and extended secondary prevention of deep vein thrombosis, and superior to warfarin for prevention of venous thromboembolism after major orthopaedic surgery. Major bleeding with melagatran/ximelagatran occurred at rates similar to those in patients treated with warfarin. 6%-12% of patients taking ximelagatran develop asymptomatic elevated liver enzyme levels (predominantly alanine aminotransferase) after 1-6 months of therapy; this usually resolves with cessation of therapy. Less than 1% of patients develop abnormal liver function while taking ximelagatran; this rarely persists or develops into clinical illness.

Topics: Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Glycine; Humans; Myocardial Infarction; Secondary Prevention; Stroke; Thrombin; Treatment Outcome; Venous Thrombosis

A new generation of antithrombotic agents that target a single enzyme within the procoagulant cascade is making its way into mainstream clinical practice. Borrowing selectively from the properties of their parent anticoagulant, unfractionated heparin, as well as from those of peptide anticoagulants from reptile or insect venoms, designers of the new drugs have created targeted inhibitors of thrombin, factor Xa, or other specific factors in the procoagulant pathways. These new agents promise efficacy and safety profiles far more favorable than those of conventional anticoagulants for thromboprophylaxis after major orthopedic surgery and require no laboratory monitoring of drug efficacy in this setting. Ximelagatran, the oral "prodrug" of the direct thrombin inhibitor melagatran, is in phase III of clinical development. Clinical trials using various dosages of ximelagatran, sometimes preceded by subcutaneous melagatran, as thromboprophylaxis after total hip or knee replacement surgery have suggested efficacy equal to or better than that of warfarin and enoxaparin. The best dosing regimen and optimal timing of first dose for melagatran and ximelagatran remain to be determined, as do the mechanism and impact of drug disturbance of hepatic function. Fondaparinux, a selective, synthetic inhibitor of factor Xa, has been shown in large clinical trials to be superior to low-molecular-weight heparins and is approved as a fixed once-daily subcutaneous 2.5-mg dose for thromboprophylaxis for hip or knee replacement surgery and after hip fracture repair. Fixed-dose fondaparinux 2.5 mg initiated 6 to 8 hours after surgery achieved superior efficacy and comparable safety in head-to-head comparisons with enoxaparin for the prevention of venous thromboembolism after major orthopedic surgery. Fondaparinux is the only agent approved for use in hip fracture patients in the United States at this time and has recently gained approval for extended prophylaxis in this patient population.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Glycine; Heparin; Heparin, Low-Molecular-Weight; Humans; Models, Biological; Orthopedics; Polysaccharides; Postoperative Complications; Thromboembolism; Thrombolytic Therapy

The current management of thrombotic and vascular disorders has been strongly influenced by the introduction of several new drugs. 1. One of the major impact in the management of venous thromboembolic disorders has been the LMWHs. The newest, third generation heparin, the pentasaccharide inhibits specifically FXa. The elimination half-life of pentasaccharide is about 17 h, which allows a convenient once-daily dosing regime. The effects of pentasaccharide needs antithrombin. 2. Melagatran dipeptid is a specific, reversible direct thrombin inhibitor. It inhibits free and clot bound thrombin. Ximelagatran is a prodrug of melagatran. It is the first clinically used orally acting direct thrombin inhibitor. 3. Recombinant human activated protein C (rh-APC) has some advantages in patients with septic DIC. Qualities of the three new anticoagulants and clinical experiences with them have been summarized.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Glycine; Humans; Polysaccharides; Protein C; Pulmonary Embolism; Recombinant Proteins; Venous Thrombosis

Venous thromboembolism is a common and potentially fatal complication among hospital in-patients, particularly those undergoing orthopaedic surgery. Current prophylactic strategies utilise low molecular weight heparins (LMWHs) and warfarin. However, painful subcutaneous injections for LMWHs and delays in achieving target anticoagulation for warfarin pose significant problems clinically. The Melagatran for THRombin inhibition in Orthopaedic surgery (METHRO) trial represents a landmark step in the sequential combination of subcutaneous and oral anticoagulation with melagatran and ximelagatran, respectively, for surgical venous thromboprophylaxis. These agents have proven to be as effective and safe as LMWHs. Furthermore, with no need for dosage adjustment or therapeutic drug monitoring there is emerging evidence that ximelagatran may replace warfarin as the anticoagulant of choice.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Humans; Orthopedic Procedures; Prodrugs; Thrombin; Venous Thrombosis

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 alpha-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.

Topics: Azetidines; Benzylamines; Glycine; Hemostasis; Humans; Pharmacokinetics; Prodrugs; Thrombin; Thrombosis

The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (MElagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Humans; Orthopedic Procedures; Thromboembolism; Thrombosis; Treatment Outcome

There are many well-known drawbacks associated with the currently used antithrombotic agents, warfarin, heparin, and low-molecular-weight heparins (LMWHs). Because heparins can be administered only parenterally, their application is limited. Though warfarin can be administered orally, its unpredictable anticoagulant effect means that it must be regularly monitored. Ximelagatran (Exanta, AstraZeneca) is a novel, oral direct thrombin inhibitor (oral DTI) that is rapidly converted to its active form, melagatran, upon administration. The antithrombotic effects of melagatran have been demonstrated. Following the oral administration of ximelagatran, melagatran has stable and reproducible pharmacokinetic and pharmacodynamic properties that enable ximelagatran to be administered orally, twice daily, according to a fixed-dose regimen, with no need for routine coagulation monitoring. In view of its favourable profile, a clinical trial programme has been designed to evaluate the efficacy and tolerability of ximelagatran compared with standard therapies, for the prophylaxis and treatment of venous thromboembolism (VTE), the prevention of stroke in patients with atrial fibrillation (AF), and the prevention of cardiovascular events in patients with previous acute coronary syndromes. These studies show that oral ximelagatran is well tolerated at doses of up to 60 mg, twice daily (bid), and that it is as effective as standard therapy for the prevention of thromboembolic events in patients undergoing hip or knee replacement surgery, for the treatment of clinically verified acute deep vein thrombosis (DVT), and in patients with nonvalvular AF who have a moderate to high risk of stroke. 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.

Topics: Azetidines; Benzylamines; Cardiovascular Diseases; Clinical Protocols; Clinical Trials as Topic; Glycine; Humans; Thromboembolism

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.

Topics: Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Glycine; Hemostasis; Humans; Prodrugs; Pyridines; Stroke; Thrombin; Thrombosis; Venous Thrombosis; Vitamin K

Two new classes of anticoagulants are actually developed which would change in the near future our strategies for the prevention and the treatment of venous thromboembolic events. These two classes are the anti-factor Xa and anti-factor IIa (direct antithrombin) agents. Among the anti factor Xa, the pentasaccharides are initiating their clinical use. Fondaparinux is a synthetic form of the natural pentasaccharide, its pharmacokinetics allows one s.c. administration/24 hours. It is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. A modified form (idraparinux) whose pharmacokinetics allows one administration only once a week should have the same type of efficacy. Among direct antithrombin agents, hirudin and derivatives have been developed in the past decade with a limited use due to several drawback. More recently synthetic direct antithrombins modified to allow oral route have been developed, the most advanced in development, melagatran, is active in the prevention and treatment of venous thromboembolic and coronary thrombotic events. It could allow (if confirmed by clinical trials) a complete oral treatment of deep vein thrombosis without any biological monitoring. Melagatran is also active in the prevention of arterial thromboembolic events on atrial fibrillation. But other molecular forms of synthetic orally active direct antithrombin are also in development. Besides these important changes in our therapeutics which should appear in a near future, molecules aimed at other target are also tested: the most advanced are those antagonizing the initial phase of tissue factor activation of factor VII but other strategies are being tested such as stimulation of fibrinolysis. These new drugs at our disposal to treat venous thromboembolism should modify completely our handling of the patients. But additionally the numerous clinical trials necessary to prove the efficacy of the drugs, modify our understanding in the implication of the coagulation and in the physiopathogeny of thrombotic events.

Topics: Administration, Oral; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Thrombosis; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Hirudin Therapy; Humans; Orthopedics; Polysaccharides; Prodrugs; Prothrombin; Research; Thrombin; Thromboembolism; Time Factors; Venous Thrombosis

Melagatran is a direct inhibitor of thrombin and-like its oral prodrug ximelagatran-a newly developed dipetide with high antithrombotic efficacy. They present a linear dose-response, a short plasma half-life and the therapeutic range may be advantageous compared with classic anticoagulants such as heparins or vitamin K antagonists. The results of clinical studies for prevention and treatment of thromboembolic complications are encouraging. The use of melagatran and ximelagatran will gain significance in the perioperative management, thus being of particular importance for anaesthesiology and critical care medicine in the near future.

Topics: Anesthesia; Animals; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Fibrinolytic Agents; Glycine; Half-Life; Humans

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action. Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1). reviews the limitations of vitamin K antagonists, (2). lists the characteristics of an ideal anticoagulant, (3). rationalizes thrombin as a target for new anticoagulants, (4). reviews the preclinical and clinical data with ximelagatran, and (5). provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Blood Coagulation; Drug Monitoring; Glycine; Humans; International Normalized Ratio; Postoperative Complications; Prodrugs; Stroke; Thrombin; Thrombosis; Venous Thrombosis; Vitamin K

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Topics: Administration, Oral; Amino Acid Chloromethyl Ketones; Anticoagulants; Arginine; Azetidines; Benzylamines; Binding Sites; Biological Availability; Blood Coagulation; Comorbidity; Coumarins; Drug Design; Embolism; Female; Forecasting; Glycine; Guanidines; Heart Diseases; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudin Therapy; Humans; Neoplasms; Pipecolic Acids; Pregnancy; Pregnancy Complications, Hematologic; Prodrugs; Safety; Serine; Stroke; Sulfonamides; Thrombin; Thrombophilia; Thrombosis

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 (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.. 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.

Topics: Administration, Oral; Adult; Aged; Aging; Anticoagulants; Area Under Curve; Asian People; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Humans; Male; Metabolic Clearance Rate; Prodrugs; Single-Blind Method; Thrombin; White People

It was the objective of this study to compare the antithrombotic effects and bleeding profiles of the oral direct thrombin inhibitor ximelagatran, an anticoagulant, and the antiplatelet agent clopidogrel on top of steady-state acetylsalicylic acid (ASA) in a human arterial thrombosis model. Healthy male volunteers (n=62) received ASA (160 mg once daily), plus either clopidogrel for 6 days (loading dose 300 mg, then 75 mg once daily), or a single dose of ximelagatran (36 or 72 mg) on Day 6. Changes in total thrombus area (TTA) under low shear rate (LSR; 212 s(-1)) and high shear rate (HSR; 1690 s(-1)) conditions were measured, using the ex vivo Badimon perfusion chamber model pre-dose and 2 and 5 hours after dosing on Day 6, and capillary bleeding times (CBT) were determined. Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASA alone. 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). Compared with ASA alone, CBT was markedly prolonged by clopidogrel plus ASA (ratio 6.4; P<0.0001) but only slightly by ximelagatran plus ASA (72 mg ximelagatran, ratio 1.4; P=0.0010). Both drug combinations were well tolerated. 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.

Topics: Administration, Oral; Adult; Anticoagulants; Arteries; Aspirin; Azetidines; Benzylamines; Bleeding Time; Blood Coagulation; Clopidogrel; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombin; Thrombosis; Ticlopidine

In an analysis of the Melagatran Thrombosis Prophylaxis in Orthopedic Surgery (METHRO) III study, we evaluated whether concomitant administration of aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) with the direct thrombin inhibitor melagatran/ximelagatran or the low-molecular-weight heparin enoxaparin increased bleeding in patients undergoing major joint surgery. Further objectives were to compare the influence of the timing of initial postoperative administration of melagatran/ximelagatran on bleeding in orthopedic patients receiving ASA/NSAIDs and in comparison with the preoperative administration of enoxaparin. ASA or NSAIDs in conjunction with melagatran/ximelagatran or enoxaparin did not increase bleeding. Bleeding rates were not significantly different, irrespective of the timing of the initial postoperative dose of melagatran/ximelagatran (4-8 vs. 4-12 h) when compared with preoperative (12 h) administration of enoxaparin. Transfusion rates were significantly lower with administration of melagatran/ximelagatran compared with enoxaparin.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Arthroplasty; Aspirin; Azetidines; Benzylamines; Bleeding Time; Blood Loss, Surgical; Blood Transfusion; Double-Blind Method; Enoxaparin; Europe; Female; Humans; Lower Extremity; Male; Middle Aged; Platelet Aggregation Inhibitors; South Africa; Thrombosis

In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer.. Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels.. The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

Topics: Aged; Azetidines; Benzylamines; Biomarkers; Blood Coagulation; Dose-Response Relationship, Drug; Female; Fibrin; Glycine; Humans; Male; Myocardial Infarction; Partial Thromboplastin Time; Pharmacokinetics; Thrombin; Time Factors

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Blood Transfusion; Drug Therapy, Combination; Enoxaparin; Glycine; Humans; Logistic Models; Odds Ratio; Time Factors

In this randomized, 2-way crossover study, the potential for interaction was investigated between atorvastatin and ximelagatran, an oral direct thrombin inhibitor. Healthy female and male volunteers (n = 16) received atorvastatin 40 mg as a single oral dose and, in a separate study period, ximelagatran 36 mg twice daily for 5 days plus a 40-mg oral dose of atorvastatin on the morning of day 4. In the 15 subjects completing the study, no pharmacokinetic interaction was detected between atorvastatin and ximelagatran for all parameters investigated, including melagatran (the active form of ximelagatran) area under the plasma concentration versus time curve (AUC) and maximum plasma concentration, atorvastatin acid AUC, and AUC of active 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors. Atorvastatin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between atorvastatin and ximelagatran was observed in this study.

Topics: Administration, Oral; Adult; Anticholesteremic Agents; Anticoagulants; Area Under Curve; Atorvastatin; Azetidines; Benzylamines; Cross-Over Studies; Drug Combinations; Drug Interactions; Female; Glycine; Half-Life; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Partial Thromboplastin Time; Prodrugs; Pyrroles

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. On 2 separate occasions, healthy female and male volunteers (n = 16) received ximelagatran 36 mg or placebo twice daily for 8 days separated by a 4- to 14-day washout period. All volunteers received a single oral dose of digoxin 0.5 mg on day 4 of both study periods. No interaction between ximelagatran and digoxin was detected in the pharmaco-kinetic parameters (using a 90% confidence interval [CI] of least squares mean estimate ratios), including melagatran (the active form of ximelagatran) AUC(tau) and C(max) and digoxin AUC(t) and C(max). Digoxin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran was observed in this study.

Topics: Administration, Oral; Adult; Anti-Arrhythmia Agents; Anticoagulants; Area Under Curve; Azetidines; Benzylamines; Cross-Over Studies; Digoxin; Double-Blind Method; Drug Interactions; Female; Glycine; Half-Life; Humans; Male; Partial Thromboplastin Time; Prodrugs

We evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. 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. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Glycine; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Postoperative Complications; Prodrugs; Prospective Studies; Pulmonary Embolism; Safety; Thrombin; Treatment Outcome; Venous Thrombosis

To investigate the influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran.. This was an open-label, randomised, 3 x 3 crossover study with 4 study days, separated by washout periods of 7 days.. Subjects comprised 6 healthy young men (aged 20-27 years) and 12 healthy older men and women (aged 56-70 years).. 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. The primary variables were the plasma concentration of melagatran, the active form of ximelagatran, and the activated partial thromboplastin time (APTT), an ex vivo coagulation time measurement used to demonstrate inhibition of thrombin.. After oral and subcutaneous administration, ximelagatran was rapidly absorbed and biotransformed to melagatran, its active form and the dominant compound in plasma. The metabolite pattern in plasma and urine was similar in young and older subjects after both oral and subcutaneous administration of ximelagatran clearance of melagatran was correlated with renal function, resulting in about 40% (after intravenous melagatran) to 60% (after oral and subcutaneous ximelagatran) higher melagatran exposure in the older than in the young subjects. Renal clearance of melagatran, was 7.7 L/h and 4.9 L/h in the younger and older subjects, respectively. The interindividual variability inn the area under the melagatran plasma concentration-time curve was low following all regimens (coefficient variation 12-25%). The mean bioavailability of melagatran in young and older subjects was approximately 18 and 12% , respectively, following oral administration of ximalagratan, and 38 and 45%, respectively, following subcutaneous administration of ximelagatran. The bioavailability of melagatran following oral administration of ximelagatran was unaffected by whether subjects were fed or fasting, although the plasma concentration of melagatran peaked about 1 hour later under fed than fasting conditions, due to gastric emptying of the immediate-release tablet formulation used. The APTT as prolonged with increasing melagatran plasma concentration-effect relationship was independent of age.. 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.

Topics: Administration, Oral; Adult; Age Factors; Aged; Area Under Curve; Azetidines; Benzylamines; Biological Availability; Cross-Over Studies; Female; Fibrinolytic Agents; Food-Drug Interactions; Glycine; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Metabolic Clearance Rate; Middle Aged; Prodrugs; Thrombin

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.

Topics: Administration, Oral; Adult; Area Under Curve; Asian People; Azetidines; Benzylamines; Black People; Glycine; Humans; Inactivation, Metabolic; Male; Prodrugs; Racial Groups; Thrombin; White People

Ximelagatran, an oral direct thrombin inhibitor, is currently in clinical development for the prevention and treatment of thromboembolic disease. Following oral administration, ximelagatran undergoes rapid bioconversion to its active form, melagatran, via two minor intermediates. Obesity, defined as body mass index (BMI) >30 kg/m(2), is a recognised risk factor for thrombosis. There is potential for differences in the pharmacokinetics and pharmacodynamics of drugs administered to obese versus non-obese patients, and some drugs may require alternative administration strategies in obese patients.. To investigate the effect of obesity on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran.. This was an open-label, single-dose, group-matched study in which obese subjects (BMI 32-39 kg/m(2); six male and six female; age 21-40 years) were matched by sex and age (+/-2 years) with non-obese subjects (BMI 21-26 kg/m(2); six male and six female; aged 21-39 years). Each subject received a single oral dose of ximelagatran 24mg. Blood samples for determination of plasma concentrations of melagatran and activated partial thromboplastin times (APTT; a marker of melagatran pharmacodynamics) were collected up to 12 hours after administration.. There were no statistically significant differences in the pharmacokinetic properties of melagatran between obese and non-obese subjects. Values of area under the melagatran plasma concentration-time curve, maximum plasma concentration (C(max)), time at which C(max) occurred and terminal elimination half-life were approximately 1 micromol. h/L, 0.2 micromol/L, 2 hours and 3 hours in both obese and non-obese subjects, respectively. In addition, there was no statistically significant difference between the obese and non-obese subjects in the amount of ximelagatran, melagatran or the minor intermediates ethyl-melagatran and melagatran hydroxyamidine excreted in urine. When relating the prolongation of APTT ratio to the square root of plasma concentration of melagatran and obesity status (no/yes), no statistically significant interaction between plasma concentration and obesity status was observed. Ximelagatran was well tolerated in both obese and non-obese subjects, and no bleeding events or serious adverse events occurred.. No differences in the pharmacokinetics or pharmacodynamics of melagatran were detected between obese and non-obese subjects after oral administration of ximelagatran, suggesting that dose adjustment of ximelagatran in obesity (BMI up to 39 kg/m(2)) is not necessary.

Topics: Administration, Oral; Adult; Area Under Curve; Azetidines; Benzylamines; Female; Glycine; Half-Life; Humans; Inactivation, Metabolic; Male; Obesity; Thrombin

Ximelagatran is a novel, oral direct thrombin inhibitor designed to overcome the low and variable oral absorption of melagatran, its active form. The pharmacokinetics and pharmacodynamics of ximelagatran following single and repeated oral administration were investigated. The primary objectives were to determine the dose linearity and reproducibility of melagatran exposure and the influence of food intake.. Two open-label studies were performed in healthy male subjects. Study I was a dose-escalation study, in which subjects received single oral doses of ximelagatran (1-98 mg). Study II was a randomised, two-way crossover study consisting of two 5-day treatment periods, in which subjects received a 20-mg oral dose of ximelagatran twice daily, either before breakfast and with dinner, or with breakfast and after dinner.. Ximelagatran was rapidly absorbed and converted to melagatran, which was the predominant compound in plasma. The mean (+/- standard deviation) bioavailability of melagatran was 22.2+/-4.3% and 17.4+/-2.8% after single and repeated dosings, respectively. The maximum plasma concentration of melagatran and the area under the melagatran plasma concentration-time curve (AUC) increased linearly with dose. Inter- and intra-subject variability in melagatran AUC was 8% and 12%, respectively, with no relevant food- or time dependence. Anticoagulation, assessed as activated partial thromboplastin time, was correlated with melagatran plasma concentration. There was virtually no increase in capillary bleeding time over the dose range studied, and ximelagatran was well tolerated.. After oral administration of ximelagatran to healthy male subjects, the pharmacokinetic and pharmacodynamic profile of melagatran is predictable and reproducible.

Topics: Administration, Oral; Adult; Analysis of Variance; Anticoagulants; Area Under Curve; Azetidines; Benzylamines; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Food-Drug Interactions; Glycine; Half-Life; Humans; Male; Metabolic Clearance Rate; Partial Thromboplastin Time; Prodrugs; Prothrombin Time; Thrombin

The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (MElagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Humans; Orthopedic Procedures; Thromboembolism; Thrombosis; Treatment Outcome

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.. Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model.. The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT.. The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.

Topics: Administration, Cutaneous; Administration, Oral; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Biological Availability; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Glycine; Humans; Metabolic Clearance Rate; Partial Thromboplastin Time; Postoperative Complications; Sweden; Thromboembolism; Venous Thrombosis; Whole Blood Coagulation Time

The aim of this study was to evaluate the effect of acetylsalicylic acid (ASA or aspirin) on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran in healthy volunteers. Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran.. This was a double-blind, randomised, two-way, crossover study consisting of two treatment periods separated by a washout period of at least 2 weeks. Twelve subjects received, in a randomised order, either melagatran plus ASA in the first treatment period and melagatran plus placebo in the second treatment period or vice versa. Two single doses of ASA were given, first 450 mg on the day before (day 1) and then 150 mg just before administration of melagatran on day 2. Melagatran 4.12 mg was administered as an intravenous (i.v.) infusion over 4 h on day 2 of both treatment periods. Serial blood samples were collected over the course of the study for the determination of melagatran plasma concentration and coagulation analyses [activated partial thromboplastin time (APTT) and activated clotting time (ACT)]. Capillary bleeding time was measured before ASA/placebo on day 1 and before and after the start of the melagatran infusion on day 2.. The plasma concentration of melagatran during the i.v. infusion was maintained at about 0.2 micro mol/l, and ASA did not influence the PK parameters of melagatran. APTT and ACT increased with increasing melagatran plasma concentration, and the observed increases were similar whether melagatran was administered on top of ASA or placebo. Administration of ASA significantly prolonged the capillary bleeding time (by 41% relative to placebo). Melagatran also prolonged the bleeding time significantly (by 25% relative to placebo alone), but this prolongation was not significantly different from the observed prolongation when melagatran was administered on top of ASA (by 17% relative to ASA alone).. In young healthy volunteers, ASA had no effect on the PK or PD properties of melagatran at the studied dose. That the combination of ximelagatran with ASA may be used with acceptable safety must be verified in the relevant patient populations.

Topics: Administration, Oral; Adult; Aspirin; Azetidines; Benzylamines; Blood Coagulation; Cross-Over Studies; Double-Blind Method; Drug Interactions; Glycine; Humans; Infusions, Intravenous; Male; Partial Thromboplastin Time; Platelet Aggregation Inhibitors; Prodrugs; Thrombin; Whole Blood Coagulation Time

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

Ximelagatran is an oral direct thrombin inhibitor currently in clinical development as an anticoagulant 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 effect of severe renal impairment on the pharmacokinetics and pharmacodynamics of melagatran following administration of subcutaneous melagatran and oral ximelagatran.. This was a nonblinded randomised crossover study with 2 study days, separated by a washout period of 1-3 weeks. Twelve volunteers with severe renal impairment and 12 controls with normal renal function were included, with median (range) glomerular filtration rates (GFR) of 13 (5-24) and 86 (70-105) mL/min, respectively. All volunteers received, in a randomised sequence, a 3mg subcutaneous injection of melagatran and a 24mg immediate-release tablet of ximelagatran. Blood samples were collected up to 12 and 14 hours after administration of the subcutaneous and oral doses, respectively, for determination of melagatran plasma concentrations and the activated partial thromboplastin time (APTT), an ex vivo measurement of coagulation time. Urine was collected for 24 hours after each dose for determination of melagatran concentration.. For the volunteers with severe renal impairment, the area under the plasma concentration-time curve (AUC) and the half-life of melagatran were significantly higher than in the control group with normal renal function. Least-squares mean estimates of the ratios of the mean AUC for volunteers with severe renal impairment and controls (95% confidence intervals) were 4.03 (3.29-4.93) after subcutaneous melagatran and 5.33 (3.76-7.56) after oral ximelagatran. This result was related to the decreased renal clearance (CL(R)) of melagatran, which was linearly correlated with GFR. In the severe renal impairment and control groups, respectively, the mean CL(R) of melagatran was 12.5 and 81.3 mL/min after subcutaneous administration of melagatran and 14.3 and 107 mL/min after oral administration of ximelagatran. There was a nonlinear relationship between the APTT ratio (postdose/predose APTT value) and melagatran plasma concentration. A statistically significant higher slope of the concentration-effect relationship, described by linear regression of the APTT ratio versus the square root of melagatran plasma concentrations, was estimated for the group with severe renal impairment compared to the control group; however, the increase in slope was minor and the estimated differences in APTT ratio between the groups in the studied concentration range was less than 10% and not considered clincially relevant. Ximelagatran and melagatran were well tolerated in both groups.. After administration of subcutaneous melagatran and oral ximelagatran, subjects with severe renal impairment had significantly higher melagatran exposure and longer half-life because of lower CL(R) of melagatran compared with the control group with normal renal function, suggesting that a decrease in dose and/or an increase in the administration interval in patients with severe renal impairment would be appropriate.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Area Under Curve; Azetidines; Benzylamines; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Glycine; Half-Life; Humans; Injections, Subcutaneous; International Normalized Ratio; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Partial Thromboplastin Time; Prodrugs; Thrombin; Time Factors

Ximelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, ximelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-melagatran and hydroxy-melagatran), to its active form, melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of melagatran.. To investigate the potential of ximelagatran, the intermediates ethyl-melagatran and hydroxy-melagatran, and melagatran to inhibit the CYP system in vitro and in vivo, and the influence of three CYP substrates on the pharmacokinetics of melagatran in vivo.. The CYP inhibitory properties of ximelagatran, the intermediates and melagatran were tested in vitro by two different methods, using heterologously expressed enzymes or human liver microsomes. Diclofenac (CYP2C9), diazepam (CYP2C19) and nifedipine (CYP3A4) were chosen for coadministration with ximelagatran in healthy volunteers. Subjects received oral ximelagatran 24mg and/or diclofenac 50mg, a 10-minute intravenous infusion of diazepam 0.1 mg/kg, or nifedipine 60mg. The plasma pharmacokinetics of melagatran, diclofenac, diazepam, N-desmethyl-diazepam and nifedipine were determined when administered alone and in combination with ximelagatran.. No inhibition, or only minor inhibition, of CYP enzymes by ximelagatran, the intermediates or melagatran was shown in the in vitro studies, suggesting that ximelagatran would not cause CYP-mediated drug-drug interactions in vivo. This result was confirmed in the clinical studies. There were no statistically significant differences in the pharmacokinetics of diclofenac, diazepam and nifedipine on coadministration with ximelagatran. 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.. 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. 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. 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.

Topics: Administration, Oral; Adult; Aged; Amidines; Anticoagulants; Area Under Curve; Azetidines; Benzylamines; Cross-Over Studies; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Diazepam; Diclofenac; Drug Interactions; Glycine; Humans; In Vitro Techniques; Infusions, Intravenous; Microsomes, Liver; Middle Aged; Nifedipine; Nordazepam; Prodrugs; Thrombin

The effect of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran, on thrombin generation was investigated in vitro and ex vivo using a thrombin generation assay. In-vitro thrombin generation was triggered in human platelet-poor plasma by the addition of tissue factor, and the endogenous thrombin potential (ETP) was measured. The ETP IC(50) values for melagatran and the low-molecular-weight heparin dalteparin were 0.44 micromol/l and 0.06 IU/ml, respectively. In contrast to dalteparin, melagatran increased the time-to-thrombin peak in a concentration-dependent manner. ETP was also studied ex vivo in platelet-poor plasma collected from healthy male subjects (n = 54) at pre-dose and 2 h post-dose, with ximelagatran (60 mg) orally, dalteparin (120 IU/kg) subcutaneously, or control (water) orally. After ximelagatran or dalteparin administration, the time-to-thrombin peak was prolonged by 41 and 95%, and the ETP was decreased by 61 and 77%, respectively. Thus, melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, efficiently delays and inhibits the generation of thrombin in plasma both in vitro and ex vivo.

Topics: Administration, Oral; Adult; Anticoagulants; Azetidines; Benzylamines; Dalteparin; Factor Xa Inhibitors; Glycine; Humans; Inhibitory Concentration 50; Injections, Subcutaneous; Male; Reference Values; Thrombin; Time Factors; Veins

To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran.. In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing.. The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls.. The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.

Topics: Administration, Oral; Adult; Aged; Aging; Area Under Curve; Atrial Fibrillation; Azetidines; Benzylamines; Female; Glycine; Humans; Infusions, Intravenous; Male; Middle Aged; Thrombin

Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease.. In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8-11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding.. The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin.. In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Enoxaparin; Female; Glycine; Hemorrhage; Humans; Male; Middle Aged; Preoperative Care; Therapeutic Equivalency; Thrombin; Thromboembolism; Venous Thrombosis

Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE).. In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6-9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded.. Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6-9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment.. Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.

Topics: Administration, Oral; Adult; Aged; Azetidines; Benzylamines; Female; Fibrinolytic Agents; Glycine; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pharmacokinetics; Prodrugs; Pulmonary Embolism; Thrombin; Treatment Outcome; Venous Thrombosis

Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin.. Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1.00 mg, 1.50 mg, 2.25 mg, or 3.00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7-10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat.. 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37.8%], 70 [24.1%], 71 [23.7%], and 43 [15.1%]; p=0.0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ximelagatran than with dalteparin (15.1% vs 28.2%, p<0.0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group.. This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.

Topics: Adult; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dalteparin; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Glycine; Humans; Male; Middle Aged; Postoperative Complications; Prodrugs; Thromboembolism

The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (s.c.). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received s.c. melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU s.c. once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received s.c. melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the s.c. melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.

Topics: Administration, Oral; Adolescent; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dalteparin; Female; Glycine; Humans; Incidence; Injections, Subcutaneous; Male; Middle Aged; Partial Thromboplastin Time; Postoperative Complications; Prodrugs; Safety; Sweden; Thrombin; Thromboembolism; Treatment Outcome; Venous Thrombosis

Patients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

Topics: Activated Protein C Resistance; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dalteparin; DNA Mutational Analysis; Double-Blind Method; Europe; Factor V; Female; Genetic Predisposition to Disease; Genotype; Glycine; Humans; Male; Middle Aged; Postoperative Complications; Promoter Regions, Genetic; Prospective Studies; Prothrombin; Pulmonary Embolism; Risk Factors; Thrombophilia; Venous Thrombosis

In support of a study designed to better understand the liver toxicity of ximelagatran, ximelagatran, and melagatran, hydroxymelagatran and ethylmelagatran were prepared in tritium labeled form. Incorporation of tritium was achieved by hydrogen isotope exchange using Crabtree's catalyst and later with N-heterocyclic containing Ir catalyst. The tritiated product was then converted into the four target compounds to afford them in high purity and specific activity.

Topics: Amidines; Antithrombins; Azetidines; Benzylamines; Isotope Labeling; Tritium

Liver and bile secretion can be an important first-pass and clearance route for drug compounds and also the site of several drug-drug interactions. In the clinical program for ximelagatran development, an unexpected effect of erythromycin on the pharmacokinetics of the direct thrombin inhibitor ximelagatran and its metabolites was detected. This interaction was believed to be mediated by inhibition of drug transporters, which normally extrude the drug into the bile. Previous Caco-2 cell experiments indicated the involvement of an active efflux mechanism for ximelagatran, hydroxy-melagatran, and melagatran possibly mediated by P-glycoprotein (P-gp). However, the inhibitors used may not have been specific enough and the possibility that transporters other than P-gp were important in the Caco-2 cell assay cannot be excluded. In this study we used RNA interference, a post-transcriptional gene silencing mechanism in which mRNA is degraded in a sequence-specific manner, to specifically knock down P-gp or multidrug resistance-associated protein 2 (MRP2) transporters in Caco-2 cells. The data obtained from bidirectional transport studies in these cells indicate a clear involvement of P-gp but not of MRP2 in the transport of ximelagatran, hydroxy-melagatran, and melagatran across the apical cell membrane. The present study shows that short hairpin RNA Caco-2 cells are a valuable tool to investigate the contribution of specific transporters in the transcellular transport of drug molecules and to predict potential sites of pharmacokinetic interactions. The results also suggest that inhibition of hepatic P-gp is involved in the erythromycin-ximelagatran interaction seen in clinical studies.

Topics: Amidines; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azetidines; Benzylamines; Biotransformation; Caco-2 Cells; Cell Polarity; Drug Interactions; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Inverted Repeat Sequences; Lentivirus; Membrane Transport Modulators; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Thrombin

High concentrations of platelet-monocyte aggregates (PMAs) have been found in patients with myocardial infarction (MI). Oral direct thrombin inhibitors (DTIs) are under evaluation as long-term antithrombotic treatment. The aim was to evaluate whether DTIs affect the formation of platelet-leukocyte aggregates, TF expression and procoagulant microparticles (MPs).. DTIs were added to an experimental whole blood model before platelet activation with thrombin or ADP. The concentrations of PMAs, platelet-granulocyte aggregates (PGAs), the amount of platelets bound per leukocyte and MPs were investigated by flow cytometry. TF mRNA and activity were recorded in all settings. TF activity was evaluated in a MI population treated with or without an oral DTI.. In vitro, thrombin and ADP increased the formation of PMAs and PGAs as well as TF mRNA expression. DTIs reduced the amount platelets bound to monocytes (p=0.02) and to granulocytes (p=0.001) upon thrombin stimulation together with a reduction of TF mRNA. In contrast, the ADP-induced formation of PMAs, PGAs and TF mRNA was not affected by the DTIs. Both thrombin and ADP stimulation increased the amount of TF-expressing MPs, which was effectively inhibited by the DTIs (p=0.02-0.002). In the MI population, the DTI reduced the TF activity (p<0.001).. DTIs modulate the formation of PMAs, PGAs and the TF production therein. Together with a reduction of procoagulant MPs, these results may contribute to the clinical benefit found of oral DTIs. Targeting different mechanisms in platelet and coagulation activation may be of importance due to the lack of effect of DTIs on ADP-induced platelet-leukocyte aggregates and TF production.

Topics: Antithrombins; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Blood Platelets; Cell-Derived Microparticles; Dabigatran; Gene Expression; Humans; Leukocytes; Myocardial Infarction; Platelet Activation; Platelet Aggregation; RNA, Messenger; Thromboplastin

This work presents the development and validation of a fully automated quantitative analysis method of melagatran, its prodrug ximelagatran, and its major metabolites for the study of drug behavior in biofluids. The method involves online sample clean-up and enrichment on a C(4) capillary column followed by separation on a capillary C(18) column. Electrospray ionization tandem mass spectrometric detection in positive ion mode was performed with multiple reactions monitoring of eight different transients, divided into two time segments with four transients each. The structural similarity, the complexity of the matrix (pig liver extract) and the formation of isobaric fragment ions, made efficient chromatographic separation necessary. The analysis method provides valid accuracy (<9%; RSD%), precision (<8%; RSD%), linearity (<1.2 nM-1 microM; R(2)>0.999), limit of quantitation (<3.6 nM), retention repeatability (<1.2%; RSD%), selectivity, as well as analyte and column stabilities over a wide concentration range.

Topics: Animals; Anticoagulants; Azetidines; Benzylamines; Chromatography, Liquid; Liver; Reproducibility of Results; Sensitivity and Specificity; Solid Phase Extraction; Swine; Tandem Mass Spectrometry

There is a lack of suitable human in vitro systems which can predict drug hepatotoxicity that in many cases involves inflammatory responses mediated by macrophages. In the present investigation we used an in vitro model based on human THP-1 cells to evaluate the inflammatory cytokine/chemokine activation properties of ximelagatran, a drug previously shown to cause elevation of liver transferases in a subset of patients. Treatment of the cells with ximelagatran caused an intracellular accumulation of the metabolites hydroxymelagatran and melagatran. A decreased viability and increased release of the pro-inflammatory cytokines and chemokines IL-8, VEGF and MCP-1 was seen. Ximelagatran exposure caused activation of ERK1/2 and JNK as evident from determination of the phosphorylation status. In accordance, the release of IL-8 was attenuated by inhibitors of the ERK- and JNK-pathways. It is concluded that human monocytes might constitute a valuable additional in vitro model for monitoring the basis for cytotoxic action of drugs.

Topics: Amidines; Anticoagulants; Azetidines; Benzylamines; Cell Line; Cell Survival; Chemokines; Cytokines; Humans; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; Monocytes

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.. To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events.. A population pharmacokinetic model was developed based on data from three phase II studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model.. Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure.. The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Computer Simulation; Drug Administration Schedule; Drug Interactions; Female; Humans; Male; Middle Aged; Models, Biological; Prodrugs; Thrombin

This study was performed to compare the anticoagulant activity of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in umbilical cord plasma with that in adult plasma. In contrast with the most frequently administered anticoagulants, the heparins, melagatran acts independently of antithrombin (AT). As a consequence, administration of melagatran is of special interest in neonates, who have physiologically low levels of AT.. Plasma samples were activated under high (as used in standard clotting assays) and low (more comparable with the physiological milieu) coagulant challenge. In the absence of melagatran, adult plasma clotted significantly faster than umbilical cord plasma under high coagulant challenge. Conversely, under low coagulant challenge, clotting of adult plasma was significantly delayed compared with umbilical cord plasma. For both high and low coagulant challenges, clotting times increased and prothrombin fragment 1.2 and thrombin-antithrombin (TAT) formation decreased with melagatran in a concentration-dependent fashion in umbilical cord and adult plasma. With increasing melagatran concentrations, the quotient between prothrombin fragment 1.2 and TAT formation increased in adult and umbilical cord plasma under both high and low coagulant challenges.. Our in vitro results cannot be directly extrapolated to clinical efficacy, but assessing the degree of inhibition of thrombin generation may be a useful surrogate for selecting effective doses of ximelagatran for in vivo studies in neonates with thromboembolic complications.

Topics: Adult; Anticoagulants; Antithrombin III; Azetidines; Benzylamines; Blood; Blood Coagulation; Dose-Response Relationship, Drug; Fetal Blood; Glycine; Humans; Infant, Newborn; Peptide Fragments; Peptide Hydrolases; Prothrombin; Thrombin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cost-Benefit Analysis; Drug Costs; Humans; Safety; Thrombin; Thromboembolism; Warfarin

To determine the excretion of the oral direct thrombin inhibitor (oral DTI), ximelagatran, and its active form, melagatran, in human milk, and to thus evaluate the potential exposure of breastfed infants to melagatran.. An open, single dose, single centre study.. Department of Antenatal Care, Primary Health Care South Bohuslän and Institute for the Health of Women and Children, Göteborg University, Sweden.. Seven healthy Caucasian breastfeeding women who were at least two months postpartum were studied.. The concentrations of ximelagatran, its two intermediates, and melagatran were determined using liquid chromatography-mass spectrometry, with the limit of quantification of 2 nmol L(-1) for human milk and 10 nmol L(-1) for plasma concentrations.. Concentrations of ximelagatran, its intermediates and melagatran were measured in breast milk over 72 hours, and in plasma over 12 hours, after a single oral 36 mg dose of ximelagatran.. Neither ximelagatran nor its intermediates were detected in human breast milk. Only trace amounts of melagatran were detected. The mean cumulative amount of melagatran excreted into breast milk over the 72-hour period after dosing with oral ximelagatran was 0.00091% of the administered dose of ximelagatran. Ximelagatran was well tolerated, with no clinically relevant changes in laboratory variables or vital signs.. Trace levels of melagatran are excreted in human breast milk following administration of the oral DTI ximelagatran. The exposure of breastfed infants to melagatran appears to be low and is therefore unlikely to be of clinical concern.

Topics: Administration, Oral; Adult; Anticoagulants; Azetidines; Benzylamines; Breast Feeding; Female; Glycine; Humans; Lactation; Milk, Human; Postpartum Period; Puerperal Disorders; Thrombin; Thromboembolism; Venous Thrombosis

The antithrombotic and bleeding properties of the oral direct thrombin inhibitor ximelagatran and of warfarin were investigated in an experimental venous thrombosis and bleeding model in anaesthetized rats. Rats were randomized to receive ximelagatran (1-20 micromol/kg), warfarin (0.20-0.82 micromol/kg), or vehicle (tap water) once daily orally for 4 days before surgery. Thrombosis was induced by partial stenosis and application of ferric chloride to the wall of the abdominal vena cava under anaesthesia. Sixty minutes after thrombus induction, rats were sacrificed, thrombi harvested, and their fresh weight determined. Bleeding was determined as haemoglobin in fluid collected from the abdominal cavity. Blood samples were taken before thrombus induction and sacrifice for determination of coagulation parameters and plasma concentrations of melagatran, the active form of ximelagatran. Ximelagatran and warfarin dose-dependently reduced thrombus formation. The highest doses of ximelagatran and warfarin almost completely prevented thrombus formation; however, the increase in bleeding (versus vehicle) was significantly lower with the highest dose of ximelagatran than with the highest dose of warfarin. The oral direct thrombin inhibitor ximelagatran is thus as at least as effective as warfarin in the prevention of thrombus formation in this animal model, but with a wider separation between antithrombotic effects and bleeding.

Topics: Animals; Azetidines; Benzylamines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glycine; Hemorrhage; Male; Rats; Rats, Sprague-Dawley; Venae Cavae; Venous Thrombosis; Warfarin

The feedback mechanism by which melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, inhibits thrombin generation was investigated in vitro, using an endogenous thrombin potential (ETP) assay. Melagatran decreased ETP in a concentration-dependent manner and increased the time to thrombin peak. FEIBA reversed the melagatran-induced reduction in ETP in a concentration-dependent manner and marginally reduced the prolongation of the time to thrombin peak. Similar results were observed for prothrombin as were seen with FEIBA. Both activated factor V and Russell's Viper Venom-factor V activator reversed the melagatran-induced prolongation in time to thrombin peak in a concentration-dependent manner and partially restored ETP. Prothrombin, in combination with Russell's Viper Venom-factor V or activated factor V, reversed both the melagatran-induced reduction in ETP and the prolongation in time to thrombin peak, in a concentration-dependent manner. These results indicate that inhibition of thrombin-mediated amplification reactions in blood coagulation is an effective way to delay or inhibit thrombin generation.

Topics: Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Dose-Response Relationship, Drug; Enzyme Activation; Factor V; Glycine; Humans; Prodrugs; Thrombin

Topics: Anticoagulants; Aspirin; Azetidines; Benzylamines; Glycine; Humans; Platelet Aggregation Inhibitors; Prodrugs; Thrombin; Warfarin

Topics: Azetidines; Benzylamines; Glycine; Humans; Prodrugs; Thrombin; Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Dissent and Disputes; Enoxaparin; Glycine; Humans; Orthopedic Procedures; Therapeutic Equivalency; Thromboembolism; Treatment Outcome; Venous Thrombosis

Analytical methods for the determination of ximelagatran, an oral direct thrombin inhibitor, its active metabolite melagatran, and intermediate metabolites, melagatran hydroxyamidine and melagatran ethyl ester, in biological samples by liquid chromatography (LC) positive electrospray ionization mass spectrometry (MS) using selected reaction monitoring are described. Isolation from human plasma was achieved by solid-phase extraction on octylsilica. Analytes and isotope-labelled internal standards were separated by LC utilising a C(18) analytical column and a mobile phase comprising acetonitrile-4 mmol/l ammonium acetate (35:65, v/v) containing 0.1% formic acid, at a flow-rate of 0.75 ml/min. Absolute recovery was approximately 80% for ximelagatran, approximately 60% for melagatran ethyl ester and >90% for melagatran and melagatran hydroxyamidine. Limit of quantification was 10 nmol/l, with a relative standard deviation <20% for each analyte and <5% above 100 nmol/l. Procedures for determination of these analytes in human urine and breast milk, plus whole blood from rat and mouse are also described.

Topics: Animals; Antithrombins; Azetidines; Benzylamines; Chromatography, Liquid; Glycine; Humans; Mice; Milk, Human; Rats; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

Heparin and Vitamin K antagonists have been the only available anticoagulants for several decades. Their use has lead to significant achievements in all fields of medicine despite various shortcomings and bleeding complications. With the objective of an improved benefit-/risk ratio selective inhibitors of factor Xa (Fondaparinux) and factor IIa (Ximelagatran) have been developed. Ximelagatran can also be orally administered. The results obtained from various clinical trials with these compounds are extremely encouraging. Thus, a significant improvement of antithrombotic treatment may be expected by their future use in the clinical and out-patient setting.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Biological Availability; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Meta-Analysis as Topic; Polysaccharides; Prodrugs; Risk Factors; Stroke; Thrombosis

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Enoxaparin; Fibrinolytic Agents; Glycine; Humans; Phenprocoumon; Placebos; Prodrugs; Thrombin; Thromboembolism; Thrombosis; Time Factors

N-Hydroxylated amidines (amidoximes) can be used as prodrugs of amidines. The prodrug principle was developed in our laboratory for pentamidine and had been applied to several other drug candidates. One of these compounds is melagatran, a novel, synthetic, low molecular weight, direct thrombin inhibitor. To increase the poor oral bioavailability due to its strong basic amidine functionality selected to fit the arginine side pocket of thrombin, the less basic N-hydroxylated amidine was used in addition to an ethyl ester-protecting residue. The objective of this investigation was to study the reduction and the hydrolytic metabolism of ximelagatran via two mono-prodrugs (N-hydroxy-melagatran and ethyl-melagatran) to melagatran by in vitro experiments. New high-performance liquid chromatography methods were developed to analyze all four compounds. The biotransformation of ximelagatran to melagatran involving the reduction of the amidoxime function and the ester cleavage could be demonstrated in vitro by microsomes and mitochondria from liver and kidney of pig and human, and the kinetic parameters were determined. So far, one enzyme system capable of reducing N-hydroxylated structures has been identified in pig liver microsomes, consisting of cytochrome b(5), NADH-cytochrome b(5) reductase, and a P450 isoenzyme of the subfamily 2D. This enzyme system also reduces ximelagatran and N-hydroxy-melagatran. The participation of recombinant human CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4 with cytochrome b(5) and b(5) reductase in the reduction can be excluded. In summary, ximelagatran and N-hydroxy-melagatran are easily reduced by several enzyme systems located in microsomes and mitochondria of different organs.

Topics: Administration, Oral; Amidines; Animals; Azetidines; Benzylamines; Chromatography, High Pressure Liquid; Esters; Glycine; Humans; Hydrolysis; In Vitro Techniques; Kidney; Liver; Microsomes; Mitochondria, Liver; Prodrugs; Swine; Thrombin

Topics: Azetidines; Benzylamines; Clopidogrel; Fibrinolytic Agents; Glycine; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Ticlopidine; Treatment Outcome; Warfarin

The antithrombotic effects of direct (ximelagatran and hirudin) and indirect (dalteparin) anticoagulants were compared using a deep venous thrombosis (DVT) treatment model in conscious rats. Thrombus formation was induced in the inferior caval vein by total stasis plus topically applied ferric chloride. After 1-h thrombus maturation, one group of 10 rats were sacrificed and the mean thrombus weight in this group was 27.3 +/- 2.7 mg. This thrombus weight was handled as a reference to which all other results were compared. In all other groups, the total occlusion was removed after 1 h but a partial stasis was retained, permitting some blood flow around the thrombus. Groups of animals received subcutaneous (s.c.) dalteparin (200 IU/kg), s.c. hirudin (0.75 micromol/kg), one of four oral doses of ximelagatran (2.5, 5, 10 or 20 micromol/kg) or s.c. saline (control). After the 3-h treatment, mean thrombus weight in the saline group (26.5 +/- 3.3 mg) did not differ significantly from that of the reference group (27.3 +/- 2.7 mg, see above). Ximelagatran decreased thrombus weight in a dose-dependent manner, with an estimated ID(50) of 15 micromol/kg. Mean thrombus weight with the highest ximelagatran dose (11.1 +/- 1.3 mg) was similar to that with hirudin (13.0 +/- 1.5 mg). The effect of dalteparin on thrombus regression was much less pronounced (20.2 +/- 1.2 mg), compared with ximelagatran and hirudin, even though it was administered at a dose that yielded a similar activated partial thromboplastin time (APTT) prolongation. In conclusion, the results from this DVT treatment model showed that direct thrombin inhibitors ximelagatran and hirudin exhibited superior antithrombotic properties to low molecular weight heparin (LMWH).

Topics: Administration, Oral; Animals; Anticoagulants; Azetidines; Benzylamines; Dalteparin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glycine; Hirudins; Male; Prodrugs; Rats; Rats, Sprague-Dawley; Thrombosis; Venae Cavae

Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7-5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human alpha-thrombin compared with melagatran [inhibition constant (K(i)) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis.. By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Caco-2 Cells; Glycine; Humans; Intestinal Absorption; Intestinal Mucosa; Male; Prodrugs; Thrombin