Pharmacokinetics and Pharmacodynamics of Ximelagatran

ABSTRACT

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 ∼20% with low inter- and intra-individual variability. Peak plasma melagatran concentrations are reached ∼2 hours after oral dosing of ximelagatran to healthy volunteers, and melagatran is eliminated with a half-life of ∼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.

Ximelegatran - pharmacokinetics - pharmacodynamics - oral direct thrombin inhibitor

REFERENCES

• 1 Atrial Fibrillation Investigators . Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.  Arch Intern Med. 1994;  154 1449-1457
• 2 Geerts W H, Pineo G F, Heit J A et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 338S-400S
• 3 Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review.  Thromb Res. 2003;  109(Suppl 1) 9-15
• 4 Hull R, Hirsh J, Jay R et al.. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.  N Engl J Med. 1982;  307 1676-1681
• 5 Odén A, Fahlén M. Oral anticoagulation and risk of death: a medical record linkage study.  BMJ. 2002;  325 1073-1075
• 6 Gustafsson D, Antonsson T, Bylund R et al.. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes.  Thromb Haemost. 1998;  79 110-118
• 7 Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.  Thromb Res. 1999;  94 187-197
• 8 Hirsh J, Dalen J, Anderson D R et al.. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.  Chest. 2001;  119 8S-21S
• 9 Gustafsson D, Nystrom J, Carlsson S et al.. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.  Thromb Res. 2001;  101 171-181
• 10 Gustafsson D, Bylund R, Antonsson T et al.. A new oral anticoagulant: the 50-year challenge.  Nat Rev Drug Discov. 2004;  3 649-659
• 11 Eriksson U G, Bredberg U, Hoffmann K J et al.. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans.  Drug Metab Dispos. 2003;  31 294-305
• 12 Eriksson U G, Bredberg U, Gislén K et al.. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects.  Eur J Clin Pharmacol. 2003;  59 35-43
• 13 Johansson L C, Frison L, Logren U, Fager G, Gustafsson D, Eriksson U G. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 381-392
• 14 Johansson L C, Andersson M, Fager G, Gustafsson D, Eriksson U G. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers.  Clin Pharmacokinet. 2003;  42 475-484
• 15 Schützer K M, Wall U, Lönnerstedt C et al.. Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation.  Curr Med Res Opin. 2004;  20 325-331
• 16 Johansson S, Wåhlander K, Larson G, Ohlsson L, Larsson M, Eriksson U G. Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men.  Blood Coagul Fibrinolysis. 2003;  14 677-684
• 17 Eriksson B I, Arfwidsson A C, Frison L et al.. 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. MElagatran for THRombin inhibition in Orthopaedic surgery.  Thromb Haemost. 2002;  87 231-237
• 18 Eriksson U G, Mandema J W, Karlsson M O et al.. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis.  Clin Pharmacokinet. 2003;  42 687-701
• 19 Eriksson B I, Ogren M, Eriksson U G et al.. Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from phase II studies.  Thromb Res. 2002;  105 371-378
• 20 Wolzt M, Wollbratt M, Svensson M, Wåhlander K, Grind M, Eriksson U G. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.  Eur J Clin Pharmacol. 2003;  59 537-543
• 21 Hellegren M, Johansson S, Eriksson U G, Wåhlander K. The oral direct thrombin inhibitor, ximelagatran, an alternative for anticoagulant treatment during the puerperium and lactation.  BJOG. 2005;  112 579-583
• 22 Mattsson C, Sarich T C, Carlsson S C. Mechanism of action of the oral direct thrombin inhibitor ximelagatran.  Semin Vasc Med. 2005;  5 235-244
• 23 Boström S L, Dagnelid E, Hansson G FH, Ulvinge J C. Inhibition of thrombin-induced feedback activation of factor V: a potential pathway for inhibition of thrombin generation by melagatran.  Blood Coagul Fibrinolysis. 2004;  15 25-30
• 24 Boström S L, Hansson G F, Sarich T C, Wolzt M. The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma.  Thromb Res. 2004;  113 85-91
• 25 Sarich T C, Wolzt M, Eriksson U G et al.. Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects.  J Am Coll Cardiol. 2003;  41 557-564
• 26 Sarich T C, Osende J I, Eriksson U G et al.. Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis.  J Thromb Haemost. 2003;  1 999-1004
• 27 Carlsson S C, Mattsson C, Eriksson U G et al.. A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays.  Thromb Res. 2005;  115 9-18
• 28 Wolzt M, Boström S L, Svensson M, Wåhlander K, Grind M, Sarich T C. Effects of the oral direct thrombin inhibitor ximelagatran on P-selectin expression and thrombin generation in atrial fibrillation.  Pathophysiol Haemost Thromb. 2003;  33 68-74
• 29 Eriksson H, Eriksson U G, Frison L et al.. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT.  Thromb Haemost. 1999;  81 358-363
• 30 Wåhlander K, Lapidus L, Olsson C G et al.. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis.  Thromb Res. 2002;  107 93-99
• 31 Bergqvist D, Solhaug J H, Holmdahl L, Eriksson U G, Andersson M, Ögren M. Pharmacokinetics, preliminary efficacy and safety of subcutaneous melagatran and oral ximelagatran: a multicentre study of thromboprophylaxis in elective abdominal surgery.  Clin Drug Invest. 2004;  24 127-136
• 32 Cullberg M, Eriksson U G, Wåhlander K, Eriksson H, Schulman S, Karlsson M O. Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis.  Clin Pharmacol Ther. 2005;  77 279-290
• 33 Wolzt M, Levi M, Sarich T C et al.. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers.  Thromb Haemost. 2004;  91 1090-1096
• 34 Eriksson U G, Samuelsson O, Attman P O et al.. Melagatran is efficiently eliminated by hemodialysis in uremic patients. Presented at the 18th International Congress on Thrombosis June 20-24, 2004 Ljubljana, Slovenia Poster PO073
• 35 Sarich T C, Teng R, Peters G R et al.. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran.  Clin Pharmacokinet. 2003;  42 485-492
• 36 Wåhlander K, Eriksson-Lepkowska M, Frison L, Fager G, Eriksson U G. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 755-764
• 37 Wernevik L C, Nyström P, Johnsson G, Nakanishi T, Eriksson U G. Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran in young healthy Japanese men.  Clin Pharmacokinet. 2005;  , In press
• 38 Eriksson U G, Johansson S, Attman P O et al.. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.  Clin Pharmacokinet. 2003;  42 743-753
• 39 Carlsson S C, Attman P O, Samuelsson O. Antithrombotic effects and pharmacokinetics of the direct thrombin inhibitor melagatran administered in dialysate in a porcine model of hemodialysis. Presented at Renal Week October 27-November 1, 2004 St. Louis, MO; Abstract SU-PO474
• 40 Attman P O, Ottosson P, Samuelsson O, Eriksson-Lepkowska M, Fager G. Prevention of clot formation during haemodialysis using the direct thrombin inhibitor melagatran in patients with chronic uraemia.  Nephrol Dial Transplant. 2005;  20 1889-1997