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David Gustafsson - One of the best experts on this subject based on the ideXlab platform.
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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.
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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
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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.
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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.
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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.
Joachim Stangier - One of the best experts on this subject based on the ideXlab platform.
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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
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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.
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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.
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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.
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the metabolism and disposition of the oral direct Thrombin Inhibitor dabigatran in humans
Drug Metabolism and Disposition, 2008Co-Authors: Stefan Blech, Joachim Stangier, Thomas Ebner, Eva Ludwigschwellinger, Willy RothAbstract:The pharmacokinetics and metabolism of the direct Thrombin Inhibitor dabigatran (BIBR 953 ZW, beta-alanine, N-[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl) were studied in 10 healthy males, who received 200 mg of [(14)C]dabigatran etexilate (BIBR 1048 MS, the oral prodrug of dabigatran) or an i.v. infusion of 5 mg of [(14)C]dabigatran. Radioactivity was measured in plasma, urine, and feces over 1 week. The metabolite pattern was analyzed by high-performance liquid chromatography with on-line radioactivity detection, and metabolite structures were elucidated by mass spectrometry. Dabigatran etexilate was rapidly converted to dabigatran, with peak plasma dabigatran concentrations being attained after approximately 1.5 h; the bioavailability of dabigatran after p.o. administration of dabigatran etexilate was 7.2%. Dabigatran was predominantly excreted in the feces after p.o. treatment and in the urine after i.v. treatment. The mean terminal half-life of dabigatran was approximately 8 h. The predominant metabolic reaction was esterase-mediated hydrolysis of dabigatran etexilate to dabigatran. Phase I metabolites accounted for
Karin Wahlander - One of the best experts on this subject based on the ideXlab platform.
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exposure response for biomarkers of anticoagulant effects by the oral direct Thrombin Inhibitor azd0837 in patients with atrial fibrillation
British Journal of Clinical Pharmacology, 2015Co-Authors: Bengt Hamren, Ulf G. Eriksson, Gregory Y H Lip, Lars Hvilsted Rasmussen, Bertil S Olsson, Eva C Jensen, Karin WahlanderAbstract:AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible Thrombin Inhibitor.
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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.
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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.
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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 an...
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pharmacokinetics and anticoagulant effect of the direct Thrombin Inhibitor melagatran following subcutaneous administration to healthy young men
Blood Coagulation & Fibrinolysis, 2003Co-Authors: Susanne Johansson, Marita Larsson, Karin Wahlander, Goran Larson, Lis Ohlsson, Ulf ErikssonAbstract:The pharmacokinetic dose linearity and reproducibility, the effects on ex-vivo coagulation time assays and bleeding time, and tolerability of the direct Thrombin Inhibitor melagatran following subcutaneous (s.c.) dosing were investigated in two open-label studies in healthy males: (i). a dose-escalation study in which subjects received single s.c. doses of melagatran (0.1-5 mg); and (ii). a repeated-dosing study in which 3 mg s.c. melagatran was administered at 12-h intervals for 4 days. In both studies, melagatran was rapidly absorbed with maximum plasma concentrations (C(max)) observed about 0.5 h post dosing. The half-life of melagatran was about 2 h. The area under the melagatran plasma concentration versus time curve increased linearly with dose. No time dependency in the area under the curve or Cmax was observed over 4 days of twice-daily dosing. The variability in pharmacokinetic parameters was low and the bioavailability of melagatran appeared to be complete. There was a steep and linear prolongation of Thrombin time, a non-linear prolongation of both activated partial thromboplastin time and activated coagulation time, and a decrease in proThrombin complex activity with increasing melagatran plasma concentration. Only moderate increases in capillary bleeding time were observed with s.c. doses up to 5 mg melagatran. Melagatran was well tolerated after s.c. injection, with good local tolerability at the injection site.
Ulf G. Eriksson - One of the best experts on this subject based on the ideXlab platform.
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exposure response for biomarkers of anticoagulant effects by the oral direct Thrombin Inhibitor azd0837 in patients with atrial fibrillation
British Journal of Clinical Pharmacology, 2015Co-Authors: Bengt Hamren, Ulf G. Eriksson, Gregory Y H Lip, Lars Hvilsted Rasmussen, Bertil S Olsson, Eva C Jensen, Karin WahlanderAbstract:AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible Thrombin Inhibitor.
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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.
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population modelling of the effect of inogatran at Thrombin Inhibitor on ex vivo coagulation time aptt in healthy subjects and patients with coronary artery disease
British Journal of Clinical Pharmacology, 2008Co-Authors: Marie Cullberg, Marita Larsson, Ulf G. Eriksson, Mats O KarlssonAbstract:Population modelling of the effect of inogatran, at Thrombin Inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
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utility of ecarin clotting time an ex vivo coagulation test for pharmacokinetic analysis of the direct Thrombin Inhibitor melagatran
2006Co-Authors: Marie Cullberg, Ulrika Wahlby, Mats O Karlsson, Ulf G. ErikssonAbstract:Utility of ecarin clotting time, an ex vivo coagulation test, for pharmacokinetic analysis of the direct Thrombin Inhibitor melagatran
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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.
Jan Kihlberg - One of the best experts on this subject based on the ideXlab platform.
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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.
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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