The Experts below are selected from a list of 2790 Experts worldwide ranked by ideXlab platform
Joachim Stangier - One of the best experts on this subject based on the ideXlab platform.
-
A: Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral Direct Thrombin Inhibitor. Clin Appl Thromb Hemost 2009, 15(Suppl 1):9S–16S
2016Co-Authors: Joachim Stangier, Andreas ClemensAbstract:Dabigatran etexilate is a novel, oral reversible Direct Thrombin Inhibitor that is rapidly absorbed and converted to its active form, dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible Inhibitor of Thrombin, inhibiting both Thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration. The elimina-tion half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug–drug interac-tions. The pharmacokinetic profile of dabigatran is consistent across a broad range of different patient populations and is unaf-fected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes
-
dabigatran etexilate a novel reversible oral Direct Thrombin Inhibitor interpretation of coagulation assays and reversal of anticoagulant activity
Thrombosis and Haemostasis, 2010Co-Authors: Joachim Stangier, Sebastian Haertter, Karlheinz Liesenfeld, Wolfgang Wienen, Martin Feuring, Andreas ClemensAbstract:Summary Dabigatran etexilate is an oral, reversible Direct Thrombin Inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, Thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot ® Thrombin Inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. ProThrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran
-
pharmacology pharmacokinetics and pharmacodynamics of dabigatran etexilate an oral Direct Thrombin Inhibitor
Clinical and Applied Thrombosis-Hemostasis, 2009Co-Authors: Joachim Stangier, Andreas ClemensAbstract:Dabigatran etexilate is a novel, oral reversible Direct Thrombin Inhibitor that is rapidly absorbed and converted to its active form, dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible Inhibitor of Thrombin, inhibiting both Thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration. The elimination half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug-drug interactions. The pharmacokinetic profile of dabigatran is consistent across a broad range of different patient populations and is unaffected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes.
-
pharmacology pharmacokinetics and pharmacodynamics of dabigatran etexilate an oral Direct Thrombin Inhibitor
Clinical and Applied Thrombosis-Hemostasis, 2009Co-Authors: Joachim Stangier, Andreas ClemensAbstract:Dabigatran etexilate is a novel, oral reversible Direct Thrombin Inhibitor that is rapidly absorbed and converted to its active form, dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible Inhibitor of Thrombin, inhibiting both Thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration. The elimination half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug-drug interactions. The pharmacokinetic profile of dabigatran is consistent across a broad range of different patient populations and is unaffected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes.
-
Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate
Clinical Pharmacokinetics, 2008Co-Authors: Joachim StangierAbstract:The Direct Thrombin Inhibitor dabigatran etexilate is currently in phase III of development for the prophylaxis and treatment of thromboembolic disorders, with three trials completed in primary venous thromboembolism (VTE) prevention. Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and converted to the active form, dabigatran. Dabigatran has been shown to specifically and reversibly inhibit Thrombin, the key enzyme in the coagulation cascade. Studies in healthy volunteers and in patients undergoing orthopaedic surgery have indicated that dabigatran has a predictable pharmacokinetic/pharmacodynamic profile, allowing for a fixed-dose regimen. Peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration in healthy volunteers, with no unexpected accumulation of drug concentrations upon multiple dosing. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. The small differences in dabigatran pharmacokinetics associated with age and gender are attributed to variations in renal function. Additional studies have shown that the pharmacokinetic/pharmacodynamic profile of dabigatran is consistent across a range of patient populations, with no effect of moderate hepatic impairment being observed. Drug-drug interactions are not observed with concomitant administration of atorvastatin, diclofenac or digoxin. The pharmacodynamic profile of dabigatran demonstrates effective anticoagulation combined with a low risk of bleeding. Further phase III studies are ongoing, including acute VTE treatment and stroke prevention in atrial fibrillation; the results obtained so far show that dabigatran etexilate is well tolerated and effective in the treatment and prevention of thromboembolic events.
David Gustafsson - One of the best experts on this subject based on the ideXlab platform.
-
macrocyclic prodrugs of a selective nonpeptidic Direct Thrombin Inhibitor display high permeability efficient bioconversion but low bioavailability
Journal of Medicinal Chemistry, 2016Co-Authors: Vincent Andersson, David Gustafsson, Fredrik Bergstrom, Jonas Branalt, Gunnar Gronberg, Staffan Karlsson, Polla Magnus, Joakim Bergman, Jan KihlbergAbstract:The only oral Direct Thrombin Inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar Direct Thrombin Inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic Thrombin Inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar Direct Thrombin Inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.
-
Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability
2016Co-Authors: Vincent Andersson, David Gustafsson, Staffan Karlsson, Joakim Bergman, Fredrik Bergström, Jonas Brånalt, Gunnar Grönberg, Magnus Polla, Jan KihlbergAbstract:The only oral Direct Thrombin Inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar Direct Thrombin Inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic Thrombin Inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar Direct Thrombin Inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not
-
the pharmacodynamics and pharmacokinetics of the oral Direct Thrombin Inhibitor ximelagatran and its active metabolite melagatran a mini review
Thrombosis Research, 2003Co-Authors: David GustafssonAbstract:Abstract Ximelagatran (Exanta™, AstraZeneca) is a novel, oral Direct Thrombin Inhibitor (oral DTI) that is rapidly converted to melagatran, its active form, following absorption. Melagatran has been shown to be a potent, rapidly binding, competitive Inhibitor of human α-Thrombin that inhibits both Thrombin activity and generation. Melagatran also effectively inhibits both free and clot-bound Thrombin. Melagatran has a wide therapeutic interval that enables it to be administered safely across a wide range of doses with no increased risk of bleeding, in contrast with warfarin whose narrow therapeutic window necessitates monitoring of its pharmacodynamic effect. Although melagatran has all the pharmacodynamic properties required of a new antithrombotic agent, low oral bioavailability that is even further reduced by the concomitant intake of food precludes its development as an oral agent. It was this that propelled the development of its prodrug, ximelagatran, which is 170 times more lipophilic than melagatran and uncharged at intestinal pH. Ximelagatran is therefore much better than melagatran at penetrating the gastrointestinal barrier and, as a consequence, has sufficient bioavailability (20%) for oral administration. Moreover, its pharmacokinetic properties following oral administration are stable and reproducible, with no food interactions and a low potential for drug–drug interactions. These properties allow ximelagatran to be administered twice daily according to a fixed dose regimen without coagulation monitoring. As a consequence of its favourable pharmacokinetic and pharmacodynamic properties, ximelagatran is currently undergoing full-scale clinical development for the prophylaxis and treatment of thromboembolic disorders.
-
absorption distribution metabolism and excretion of ximelagatran an oral Direct Thrombin Inhibitor in rats dogs and humans
Drug Metabolism and Disposition, 2003Co-Authors: Ulf G. Eriksson, Ulf Bredberg, Kurtjurgen Hoffmann, Gunnar Fager, Anneli Thuresson, Margareth Gabrielsson, Hans Ericsson, Martin Ahnoff, Kristina Gislen, David GustafssonAbstract:The absorption, metabolism, and excretion of the oral Direct Thrombin Inhibitor, ximelagatran, and its active form, melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. Ximelagatran was rapidly absorbed and metabolized following oral administration, with melagatran as the predominant compound in plasma. Two intermediates (ethyl-melagatran and OH-melagatran) that were subsequently metabolized to melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. Ximelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of ximelagatran. Appreciable quantities of ethyl-melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract, as demonstrated when ximelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of melagatran following oral administration of ximelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of ximelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of melagatran.
-
effects of ximelagatran an oral Direct Thrombin Inhibitor r hirudin and enoxaparin on Thrombin generation and platelet activation in healthy male subjects
Journal of the American College of Cardiology, 2003Co-Authors: Troy C Sarich, Ulf G. Eriksson, Michael Wolzt, Christer Mattsson, Gunnar Fager, Magnus Andersson, Maria Wollbratt, Alice Schmidt, Susanne Elg, David GustafssonAbstract:Abstract Objectives The effects of ximelagatran, an oral Direct Thrombin Inhibitor (DTI), recombinant hirudin (r-hirudin) and enoxaparin on Thrombin generation and platelet activation were studied in humans. Background Recombinant hirudin (parenteral DTI) and enoxaparin (low molecular weight heparin) have been demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism. The shed blood model allows for the study of Thrombin generation and platelet activation in humans in vivo. Methods This was an open-label, parallel-group study involving 120 healthy male volunteers randomized to receive one of three oral doses of ximelagatran (15, 30 or 60 mg), r-hirudin (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically effective in acute coronary syndromes, or to serve as a control. Thrombin generation (proThrombin fragment 1+2 [F1+2] and Thrombin-antiThrombin complex [TAT]) and platelet activation (β-thromboglobulin [β-TG]) biomarkers were studied using a shed blood model involving blood collection from skin incisions made using standardized bleeding time devices. Results Oral ximelagatran, intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p Conclusions Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both Thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model. The inhibition of Thrombin generation by 60 mg ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes.
Bengt I Eriksson - One of the best experts on this subject based on the ideXlab platform.
-
effects of the Direct Thrombin Inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients a population model analysis
British Journal of Clinical Pharmacology, 2006Co-Authors: Karlheinz Liesenfeld, Bengt I Eriksson, Hans Gunter Schafer, Inaki F Troconiz, Christiane Tillmann, Joachim StangierAbstract:AIMS: To describe the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of the Direct Thrombin Inhibitor dabigatran in hip replacement patients by assessing coagulation parameters activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT), interindividual variability and factors affecting PD responses. METHODS: BISTRO I patients received oral dabigatran etexilate postsurgery for 6-10 days. Dabigatran plasma concentrations and aPTT/ECT were measured on the day of surgery, on subsequent days and at steady state. PK-PD characteristics of the dabigatran-aPTT/ECT relationships were evaluated using NONMEM V. RESULTS: The dabigatran concentration-aPTT relationship was described combining a linear and an E(max) model. Mean baseline aPTT was 33.4 s and E(max) (maximum increase in aPTT contributed by the E(max) model) was 26.9 s. The dabigatran concentration needed to attain 50% of maximum effect (EC(50)) was 94.7 ng ml(-1) and the mean slope of the linear concentration-response relationship (SLOP) was 0.0509 s ng(-1) ml(-1). Baseline aPTT and E(max) were highest following surgery and declined with time. The dabigatran concentration-ECT relationship fitted a linear model. Mean baseline ECT was 28 s and decreased with time; 50% of the maximum effect was observed after 2.9 days. SLOP decreased from 0.38 to 0.27 s ng(-1) ml(-1) with a half-life of 1.1 day, indicating greater PD effects on the day of surgery. Interindividual and residual variability was low. Covariates could not explain variability of this model. CONCLUSIONS: aPTT and ECT prolongation were Directly correlated with dabigatran concentrations. Blood coagulation prolongation was most pronounced following surgery. Data suggest that ECT provides a more precise description of the anticoagulant effect than aPTT.
-
pharmacokinetic profile of the oral Direct Thrombin Inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement
The Journal of Clinical Pharmacology, 2005Co-Authors: Joachim Stangier, Hildegard Stahle, Karin Rathgen, Gerhard Nehmiz, Bengt I Eriksson, Ola E Dahl, Lennart Ahnfelt, Robbyna SvardAbstract:Dabigatran etexilate is an oral low-molecular-weight Direct Thrombin Inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran. The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump Inhibitor, pantoprazole. In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement. In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity). A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole. In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours. The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study. Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations. In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole. Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule. These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials.
-
a new oral Direct Thrombin Inhibitor dabigatran etexilate compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement the bistro ii randomized trial
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Bengt I Eriksson, Joachim Stangier, Ola E Dahl, Lennart Ahnfelt, Nadia Rosencher, Rohan Hettiarachchi, Harry R Buller, M L Bravo, F Piovella, Peter KaleboAbstract:Summary. Background: Dabigatran etexilate is an oral Direct Thrombin Inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. Methods: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6–10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1–4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. Results: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). Conclusions: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.
-
dose escalating safety study of a new oral Direct Thrombin Inhibitor dabigatran etexilate in patients undergoing total hip replacement bistro i
Journal of Thrombosis and Haemostasis, 2004Co-Authors: Bengt I Eriksson, Joachim Stangier, Gerhard Nehmiz, Ola E Dahl, Lennart Ahnfelt, Peter Kalebo, Karin Hermansson, V KohlbrennerAbstract:Summary. Background: Dabigatran etexilate (BIBR 1048) is an oral Direct Thrombin Inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). Objectives: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. Methods: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4–8 h after surgery, for 6–10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose–response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.
-
dose escalating safety study of a new oral Direct Thrombin Inhibitor dabigatran etexilate in patients undergoing total hip replacement bistro i
Journal of Thrombosis and Haemostasis, 2004Co-Authors: Bengt I Eriksson, Joachim Stangier, Gerhard Nehmiz, Ola E Dahl, Lennart Ahnfelt, Peter Kalebo, Karin Hermansson, V KohlbrennerAbstract:Summary. Background: Dabigatran etexilate (BIBR 1048) is an oral Direct Thrombin Inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). Objectives: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. Methods: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4–8 h after surgery, for 6–10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose–response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.
Karin Wahlander - One of the best experts on this subject based on the ideXlab platform.
-
oral Direct Thrombin Inhibitor azd0837 for the prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation a phase ii study of azd0837 in patients who are appropriate for but unable or unwilling to take vitamin k antagonist therapy
Thrombosis Research, 2011Co-Authors: Gregory Y H Lip, Anders Bylock, Ulf Eriksson, Sofia Zetterstrand, Bertil S Olsson, Lars Hvilsted Rasmussen, Christina Stahre, Maria Aunesjansson, Karin WahlanderAbstract:Background: Some patients with atrial fibrillation (AF) cannot be treated with vitamin K antagonists (VKAs) and will therefore not receive effective thromboprophylaxis. The primary objective of the present Phase II trial (NCT00623779) was to assess the feasibility of conducting a study with a novel oral anticoagulant, the Direct Thrombin Inhibitor AZD0837, in patients with AF unable or unwilling to take warfarin, by evaluation of dropout rates and compliance. Methods: Patients were randomised to receive AZD0837 extended-release tablets 150 mg (n = 43) or 300 mg (n = 42) once daily, or standard therapy (no treatment, aspirin 75-325 mg or clopidogrel 75 mg once daily; n = 46) for a median treatment duration of 6 weeks. Results: Reasons for patients not being treated with warfarin were: refusal or permanent cessation decided by the patient (64.8%), inability to keep international normalised ratio 2-3 over a 3-month period (23.2%), physician assessment that VKA was inappropriate (20.4%) and warfarin allergy (2.8%). Compliance with treatment (mean +/- SD) was 97.0 +/- 16.5% for AZD0837 150 mg and 99.8 +/- 11.4% for 300 mg. Compliance with study visits was high (mean 93-98%). The numbers of dropouts were four, six and three, whilst minor or clinically significant minor bleeds were reported in zero, five and two patients in the AZD0837 150 mg, 300 mg and standard-therapy groups, respectively. No major bleeds were reported. Both doses of AZD0837 reduced levels of fibrin D-dimer and prolonged activated partial thromboplastin time, ecarin clotting time and Thrombin clotting time. Conclusions: AZD0837 had a good safety profile during this study, including a low incidence of bleeding events, with effective anticoagulation on pharmacodynamic parameters. A larger study in AF patients unable or unwilling to take warfarin is feasible, as judged by compliance and dropout rates. (C) 2010 Elsevier Ltd. All rights reserved. (Less)
-
reversible elevations of serum creatinine levels but no effect on glomerular filtration during treatment with the Direct Thrombin Inhibitor azd0837
European Journal of Clinical Pharmacology, 2010Co-Authors: Kajsmarie Schutzer, Ulf G. Eriksson, Maria K Svensson, Sofia Zetterstrand, Karin WahlanderAbstract:Reversible mean increases in serum creatinine (approx. 10%) have been observed during clinical investigations of the oral Direct Thrombin Inhibitor AZD0837. The aim of this study was to evaluate whether the increase in s-creatinine is due to a decrease in renal glomerular filtration rate (GFR) or an inhibition of the tubular secretion of creatinine. Thirty healthy subjects aged 60–71 years were enrolled in an open-label, randomised, placebo-controlled, two-way crossover study (D1250C00033) in which they received AZD0837 450 mg extended-release formulation once daily for 8 days. Cimetidine was co-administered on Days 6–8 during both treatment periods. Blood and urine samples were collected for assessment of s-creatinine, s-cystatin C, endogenous creatinine clearance (CrCl) and urinary markers of renal damage. GFR was measured by the plasma clearance of iohexol. A 6% increase in mean s-creatinine, but no increase in s-cystatin C, was observed during treatment with AZD0837. Co-administration of cimetidine resulted in a 21% increase in s-creatinine. A significant decrease in CrCl was found during AZD0837 treatment compared with placebo [−5.73 ml/min; 95% confidence interval (CI) −11.3 to −0.12]. No significant difference in GFR (−1.6 ml/min/1.73 m2; 90% CI −3.7 to 0.5) was seen during treatment with AZD0837 versus placebo. No changes in renal damage markers were found during the treatment periods. An increase in s-creatinine and a decrease in CrCl, but no decrease in GFR, were found during treatment with AZD0837. These findings suggest that inhibition of the renal tubular secretion of creatinine is the likely cause of the observed increase in s-creatinine.
-
safety and tolerability of an immediate release formulation of theoral Direct Thrombin Inhibitor azd0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation
Thrombosis and Haemostasis, 2010Co-Authors: Bertil S Olsson, Lars Hvilsted Rasmussen, Arnljot Tveit, Eva C Jensen, Peter Wessman, Seva Panfilov, Karin WahlanderAbstract:AZD0837 is an investigational oral anticoagulant which is converted to the active form, AR-H067637, a selective Direct Thrombin Inhibitor. The present study, a multicentre, randomised, parallel-group, dose-guiding study, assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation (AF) patients. Two hundred fifty AF patients with at least one additional risk factor for stroke were randomised to receive either immediate-release AZD0837 (150mg twice daily [bid] or 350mg bid, blinded treatment) or dose-adjusted warfarin (international normalised ratio 2.0-3.0, open treatment) for three months. The safety and tolerability of 150mg bid AZD0837 appeared to be as good as that of warfarin. Total bleeding events were six with 150mg bid AZD0837, 15 with 350mg bid AZD0837 and eight with warfarin. Alanine aminotransferase elevations (>3xupper limit of normal) were infrequent, without apparent differences between treatment groups. A numerically higher incidence of serious adverse events was observed with 350mg bid AZD0837 compared with 150mg bid, with six of 13 being cardiac related, all with different diagnoses. An increase in mean serum creatinine of approximately 10% was observed in both AZD0837 groups, which returned to baseline after completion of therapy. There were no strokes, transient ischaemic attacks or cerebral haemorrhages with any of the treatments. In conclusion, the safety and tolerability of 150mg bid immediate-release AZD0837 appeared to be as good as that of dose-adjusted warfarin. However, larger studies will be needed to define the safety profile of AZD0837.
-
oral Direct Thrombin Inhibitor azd0837 for the prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation a randomized dose guiding safety and tolerability study of four doses of azd0837 vs vitamin k antagonists
European Heart Journal, 2009Co-Authors: Gregory Y H Lip, Ulf G. Eriksson, Bertil S Olsson, Lars Hvilsted Rasmussen, Eva C Jensen, Anders Persson, Karin WahlanderAbstract:Aims Oral anticoagulation with vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF) is effective but has significant limitations. AZD0837, a new oral anticoagulant, is a prodrug converted to a selective and reversible Direct Thrombin Inhibitor (AR-H067637). We report from a Phase II randomized, dose-guiding study (NCT00684307) to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of extended-release AZD0837 in patients with AF. Methods and results Atrial fibrillation patients ( n = 955) with ≥1 additional risk factor for stroke were randomized to receive AZD0837 (150, 300, or 450 mg once daily or 200 mg twice daily) or VKA (international normalized ratio 2–3, target 2.5) for 3–9 months. Approximately 30% of patients were naive to VKA treatment. Total bleeding events were similar or lower in all AZD0837 groups (5.3–14.7%, mean exposure 138–145 days) vs. VKA (14.5%, mean exposure 161 days), with fewer clinically relevant bleeding events on AZD0837 150 and 300 mg once daily. Adverse events were similar between treatment groups; with AZD0837, the most common were gastrointestinal disorders (e.g. diarrhoea, flatulence, or nausea). d-Dimer, used as a biomarker of thrombogenesis, decreased in all groups in VKA-naive subjects with treatment, whereas in VKA pre-treated patients, d-dimer levels started low and remained low in all groups. As expected, only a few strokes or systemic embolic events occurred. In the AZD0837 groups, mean S-creatinine increased by ∼10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase ≥3× upper limit of normal was similar for AZD0837 and VKA. Conclusion AZD0837 was generally well tolerated at all doses tested. AZD0837 treatment at an exposure corresponding to the 300 mg od dose in this study provides similar suppression of thrombogenesis at a potentially lower bleeding risk compared with dose-adjusted VKA. This study is registered with ClinicalTrials.gov, number NCT00684307.
-
secondary prevention of venous thromboembolism with the oral Direct Thrombin Inhibitor ximelagatran
The New England Journal of Medicine, 2003Co-Authors: Sam Schulman, Karin Wahlander, Torbjorn Lundstrom, Solveig Billing Clason, Henry ErikssonAbstract:BACKGROUND: For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding. METHODS: In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral Direct Thrombin Inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed. RESULTS: Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001). CONCLUSIONS: Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.
Peter Kalebo - One of the best experts on this subject based on the ideXlab platform.
-
a new oral Direct Thrombin Inhibitor dabigatran etexilate compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement the bistro ii randomized trial
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Bengt I Eriksson, Joachim Stangier, Ola E Dahl, Lennart Ahnfelt, Nadia Rosencher, Rohan Hettiarachchi, Harry R Buller, M L Bravo, F Piovella, Peter KaleboAbstract:Summary. Background: Dabigatran etexilate is an oral Direct Thrombin Inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. Methods: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6–10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1–4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. Results: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). Conclusions: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.
-
dose escalating safety study of a new oral Direct Thrombin Inhibitor dabigatran etexilate in patients undergoing total hip replacement bistro i
Journal of Thrombosis and Haemostasis, 2004Co-Authors: Bengt I Eriksson, Joachim Stangier, Gerhard Nehmiz, Ola E Dahl, Lennart Ahnfelt, Peter Kalebo, Karin Hermansson, V KohlbrennerAbstract:Summary. Background: Dabigatran etexilate (BIBR 1048) is an oral Direct Thrombin Inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). Objectives: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. Methods: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4–8 h after surgery, for 6–10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose–response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.
-
dose escalating safety study of a new oral Direct Thrombin Inhibitor dabigatran etexilate in patients undergoing total hip replacement bistro i
Journal of Thrombosis and Haemostasis, 2004Co-Authors: Bengt I Eriksson, Joachim Stangier, Gerhard Nehmiz, Ola E Dahl, Lennart Ahnfelt, Peter Kalebo, Karin Hermansson, V KohlbrennerAbstract:Summary. Background: Dabigatran etexilate (BIBR 1048) is an oral Direct Thrombin Inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). Objectives: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. Methods: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4–8 h after surgery, for 6–10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose–response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.
-
a dose ranging study of the oral Direct Thrombin Inhibitor ximelagatran and its subcutaneous form melagatran compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement methro i
Thrombosis and Haemostasis, 2002Co-Authors: Bengt I Eriksson, Lars Frison, Ulf G. Eriksson, Anders Bylock, Gunnar Fager, Annchristin Arfwidsson, Peter Kalebo, David GustafssonAbstract: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 (sc). 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 sc 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 sc 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 sc 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 sc 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.