Ximelagatran: An orally active direct thrombin inhibitor

American Journal of Health-System Pharmacy

Volumn 62, Issue 14, 2005, Pages 1451-1467

  Gulseth, Michael P ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

Author keywords

Anticoagulants; Contraindications; Dosage; Dosage schedules; Drug administration; Drugs; Excretion; Half life; Melagatran; Metabolism; Pharmacokinetics; Toxicity; Ximelagatran

Indexed keywords

ACETYLSALICYLIC ACID; ALCOHOL; AMIODARONE; AMOXICILLIN; ATORVASTATIN; AZITHROMYCIN; CEFUROXIME; CIPROFLOXACIN; DIAZEPAM; DICLOFENAC; DOXYCYCLINE; ENOXAPARIN; ERYTHROMYCIN; HEPARIN; MELAGATRAN; NIFEDIPINE; WARFARIN; XIMELAGATRAN;

ANGINA PECTORIS; BLEEDING; CLINICAL TRIAL; CORONARY ARTERY DISEASE; DIARRHEA; DRUG ABSORPTION; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG CONTRAINDICATION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDICATION; DRUG INHIBITION; DRUG MECHANISM; DRUG METABOLISM; DRUG STRUCTURE; FOOD AND DRUG ADMINISTRATION; HEADACHE; HEART ATRIUM FIBRILLATION; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; LIVER FAILURE; META ANALYSIS; NAUSEA; PRIORITY JOURNAL; REVIEW; STROKE; TOTAL KNEE REPLACEMENT; VENOUS THROMBOEMBOLISM;

EID: 22444445631     PISSN: 10792082     EISSN: None     Source Type: Journal    
DOI: 10.2146/ajhp040534     Document Type: Review

References (64)

1. Mueller RL, Scheldt S. History of drugs for thrombotic disease: discovery, development, and directions for the future. Circulation. 1994; 89:432-49.
2. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation. Chest. 2004; 126:429S-56S.
3. Geerts WH, Heit JA, Clagett GP et al. Prevention of venous thromboembolism. Chest. 2001; 199(1, suppl):132S-75S.
4. Kearon C, Gent M, Hirsh J et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999; 340: 901-7.
5. Schulman S, Granqvist S, Holmstrom M et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997; 336:393-8.
6. Kearon C, Ginsberg JS, Kovacs MJ et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003; 349:631-9.
7. Bussey HI. An overview of anticoagulants, antiplatelet agents, and the combination in patients with mechanical heart valves. J Heart Valve Dis. 2004; 13:319-24.
8. Nutescu EA, Wittkowsky AK. Direct thrombin inhibitors for anticoagulation. Ann Pharmacother. 2004; 38:99-109.
9. Ansell J, Hirsh J, Poller L et al. The pharmacology and management of the vitamin K antagonists. Chest. 2004; 126: 204S-33S.
10. Hirsh J. Current anticoagulant therapy-unmet clinical needs. Thromb Res. 2003; 109:S1-8.
11. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ. 1994; 309:1286-91.
12. Weitz JI. A novel approach to thrombin inhibition. Thromb Res. 2003; 109:S17-22.
13. Kaplan KL. Direct thrombin inhibitors. Expert Opin Pharmacother. 2003; 4:653-66.
14. 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:S9-15.
15. Sarich TC, Wolzt M, Eriksson UF 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; 41:557-64.
16. Sarich TC, Eriksson UG, Mattsson C et al. Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost. 2002; 87:300-5.
17. Gustafsson D, Nystrom JE, 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; 101:171-81.
18. Eriksson UG, Bredberg U, Hoffmann KJ 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.
19. Clement B, Lopian K. Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor, ximelagatran, an amidoxime and ester prodrug. Drug Metab Dispos. 2003; 31:645-51.
20. Eriksson UG, Bredberg U, Gislen 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.
21. Johansson LC, Frison L, Logren U et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet. 2003; 42:381-92.
22. Bredberg E, Andersson TB, Frison L et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome p450-mediated drug-drug interactions. Clin Pharmacokinet. 2003; 42:765-77.
23. Wolzt M, Wollbratt M, Svensson M et al. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol. 2003; 59:537-43.
24. Eriksson UG, Mandema JW, Karlsson MO et al. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopedic surgery patients receiving subcutaneous melagatran and oral ximelagatran, a population model analysis. Clin Pharmacokinet. 2003; 42:687-701.
25. Johansson LC, Andersson M, Fager G et al. 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; 42:475-84.
26. Sarich TC, Teng R, Peters GR 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; 42:485-92.
27. Wahlander K, Eriksson-Lepkowska M, Frison L et al. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet. 2003; 42:755-64.
28. Eriksson BI, Arfwidsson AC, 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 1. Thromb Haemost. 2002; 87:231-7.
29. Dager WE, Vondracek TG, Mcintosh BA et al. Ximelagatran: an oral direct thrombin inhibitor. Ann Pharmacother. 2004; 38:1881-97.
30. Eriksson UG, Johansson S, Attman PO et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet. 2003; 42:743-53.
31. Schutzer KM, Wall U, Lonnerstedt C et al. Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation. Curr Med Res Opin. 2004; 20:325-31.
32. Bergqvist D, Holmdahl L, Solhaug JH et al. Efficacy and safety of subcutaneous melagatran and oral ximelagatran (pINN, formerly H 376/95) as prophylaxis against thromboembolic complications following general abdominal surgery. Thromb Haemost. 2001; 86(suppl). Abstract.
33. Cohen AT, Eriksson BI, Agnelli G et al. The oral direct thrombin inhibitor ximelagatran and its active form melagatran are efficacious and well tolerated as thromboprophylaxis after total hip or total knee replacement (THR or TKR). Br J Haematol. 2002; 117(suppl 1):25. Abstract.
34. Eriksson BI, Bergqvist D, Kalebo P et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomized trial. Lancet. 2002; 360:1441-7.
35. Heit JA, Colwell CW, Francis CW et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement. Arch Intern Med. 2001; 161:2215-21.
36. Eriksson H, Wahlander K, Gustafsson D et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost. 2003; 1:41-7.
37. Wahlander K, Lapidus L, Olsson CG et al. An open-label, pilot study for the treatment of pulmonary embolism with the oral direct thrombin inhibitor ximelagatran. Blood. 2001; 98(11). Abstract.
38. Petersen P, Grind M, Adler J et al. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003; 41:1445-51.
39. Petersen P, Robinson T. A 2-year follow-up of ximelagatran as an oral direct thrombin inhibitor for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Blood Coagul Fibrinolysis. 2002; 13:A11. Abstract.
40. Wallentin, L, Wilcox RG, Weaver WD et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial. Lancet. 2003; 362:789-97.
41. Eriksson BI, Agnelli G, Cohen AT et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO III study. Thromb Haemost. 2003; 89: 288-96.
42. Eriksson BI, Agnelli G, Cohen AT et al. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost. 2003; 1:2490-6.
43. Hull RD, Pineo GF, Stein PD et al. Timing of initial administration of low molecular weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Meet. 2001; 161:1952-60.
44. Francis CW, Davidson BL, Berkowitz SD et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. Ann Intern Med. 2002; 137:648-55.
45. Colwell CW, Berkowitz SD, Davidson BL et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study. J Thromb Haemost. 2003; 1:2119-30.
46. Francis CW, Berkowitz SD, Comp PC et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003; 349:1703-12.
47. Colwell CW, Berkowitz SD, Comp PC et al. Randomized, double-blind comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR): EXULT B. Blood. 2003; 102(11, pt. 1):14A. Abstract.
48. Fiessinger JN, Huisman MV, Davidson BL et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis. JAMA. 2005; 293:681-9.
49. AstraZeneca Pharmaceuticals. Exanta (ximelagatran) tablets NDA 21-686 FDA Advisory Committee briefing document. www.fda.gov/ohrms/dockets/ac/04/ briefing/2004-4069B1_01_AstraZeneca-Backgrounder.pdf (accessed 2004 Oct 22).
50. Schulman S, Wahlander K, Lundstrom T et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003; 349:1713-21.
51. Ridker PM, Goldhaber SZ, Danielson E et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003; 348:1425-34.
52. Halperin JL; Executive Steering Committee, SPORTIF III and V Study Investigators. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V). Am Heart J. 2003; 146:431-8.
53. SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomized controlled trial. Lancet. 2003; 362:1691-8.
54. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. JAMA. 2005; 293:690-8.
55. He R. Clinical review for NDA 21-686. www.fda.gov/ohrms/dockets/ac/04/ briefing/2004-4069B1_04_ FDA-Backgrounder-MOR-180.pdf (accessed 2004 Oct 23).
56. Elkelboom J, Hankey G. Ximelagatran or warfarin in atrial fibrillation? Lancet. 2004; 363:734. Letter.
57. Vadivelu MK. Aspirin bias in SPORTIF III trial. Lancet. 2004; 363:2091. Letter.
58. AstraZeneca Pharmaceuticals. Successful outcome to the mutual recognition procedure for Exanta (ximelagatran) in Europe. www.astrazeneca.com/ pressrelease/ 1898.aspx (accessed 2004 Oct 20).
59. AstraZeneca Pharmaceuticals. Exanta (ximelagatran) regulatory filings submitted in the United States (US) and European Union (EU) for key chronic indications. www.astrazeneca.com/pressrelease/ 1096.aspx (accessed 2004 Oct 22).
60. He R. Integrated executive summary for FDA review for NDA 21-686 Exanta (ximelagatran). www.fda.gov/ohrms/ dockets/ac/04/briefing/2004-4069B1_03_FDA- Backgrounder-Execsummaryredacted.pdf (accessed 2004 Oct 23).
61. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century-Crofts; 1999.
62. Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate of recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res. 2001; 101:145-57.
63. Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee testimony, www.fda.gov/ohrms/ dockets/ac/04/transcripts/2004-4069T1. pdf (accessed 2004 Oct 24).
64. AstraZeneca receives action letter from FDA for Exanta (ximelagatran). http:// money.cnn.com/services/tickerheadlines/ prn/phf020.P1.10082004143723. 22482.htm (accessed 2004 Oct 24).