Drug-Induced Liver Injury in Humans: The Case of Ximelagatran

  • M. Keisu
  • T. B. AnderssonEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)


Ximelagatran was the first orally available direct thrombin inhibitor under clinical development that also reached the market. Ximelagatran was tested in an extensive clinical programme. Short-term use (<12 days) in humans including the phase III clinical trials did not indicate any hepatotoxic potential. Increased hepatic enzyme levels were first observed at a higher frequency when evaluating the long-term (>35 days) use of ximelagatran (incidence of >3× upper limit of normal (ULN) plasma ALT was 7.9%). The frequency of elevated total bilirubin levels was similar in the ximelagatran and the comparator groups. However, the combination of ALT > 3×ULN and total bilirubin >2×ULN was 0.5% among patients treated with ximelagatran and 0.1% among patients in the comparator group. Symptoms such as fever and rash potentially indicating hypersensitivity (immunologic type of reaction) were low and did not differ between ximelagatran and the comparators. The withdrawal of ximelagatran from the market and termination of the ximelagatran development program was triggered by safety data from a 35-day study, indicating that severe hepatic injury in a patient could develop after exposure to the drug has been completed and that regular liver function monitoring may not mitigate the possible risk of severe hepatic injury. As for many drugs causing liver injury, the standard preclinical toxicological studies provided no indication that ximelagatran affected hepatic functions. In addition, extensive investigations using human-based in vitro models have not been able to define mechanisms explaining the pattern of hepatic injury observed in long-term clinical trials. A pharmacogenomic study provided evidence that the ALT increases were associated with major histocompatibility complex (MHC) alleles DRB1’07 and DQA1*02 suggesting a possible immunogenic pathogenesis. This example provides important clues to the mechanism of idiosyncratic drug-induced liver toxicity.


Ximelagatran Thrombin inhibitor Pharmacogenetics Transaminases Bilirubin In vitro liver toxicity models 


  1. Agnelli G, Eriksson BI, Cohen AT, Bergqvist D, Dahl OE, Lassen MR, Mouret P, Rosencher N, Andersson M, Bylock A, Jensen E, Boberg B (2009) On behalf of the EXTEND Study Group. Submitted for publicationGoogle Scholar
  2. Ansell J, Hirsch J, Dahlen J, Bussey H, Anderson D, Poller L, Jacobson A, Deykin D, Matchar D (2001) Managing oral anticoagulant therapy. Chest 119(Suppl 1):22S-38SGoogle Scholar
  3. Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J (1997) HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 156:1601-1605PubMedGoogle Scholar
  4. Bredberg E, Andersson TB, Frison L, Thuresson A, Johansson S, Eriksson-Lepkowska M, Larsson M, Eriksson UG (2003) Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 42:765-777PubMedCrossRefGoogle Scholar
  5. Clement B, Lopian K (2003) Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug. Drug Met Disp 31:645-651CrossRefGoogle Scholar
  6. De Groot AS (2006) Immunomics: discovering new targets for vaccines and therapeutics. Drug Discov Today 11:203-209PubMedCrossRefGoogle Scholar
  7. Edgar AD, Tomkiewicz C, Costet P, Legendre C, Aggerbeck M, Bouguet J, Staels B, Guyomard C, Pineau T, Barouki R (1998) Fenofibrate modifies transaminase gene expression via a peroxisome proliferator activated receptor alpha-dependent pathway. Toxicol Lett 98:13-23PubMedCrossRefGoogle Scholar
  8. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, Eskilson C, Nylander I, Frison L, Ögren M (2003a) 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 89:288-296PubMedGoogle Scholar
  9. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, Rosencher N, Kälebo P, Panfilov S, Eskilson C, Andersson M (2003b) 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. Thromb Haemost 1:2490-2496CrossRefGoogle Scholar
  10. Eriksson UG, Bredberg U, Hoffmann KJ, Thuresson A, Gabrielsson M, Ericsson H, Ahnoff M, Gislén K, Fager G, Gustafsson D (2003c) Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Met Disp 31:294-305CrossRefGoogle Scholar
  11. Executive Steering committee on behalf of the SPORIF III Investigators (2003) Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 362:1691-1698CrossRefGoogle Scholar
  12. Francis CW, Davidson BL, Berkowitz SD, Lotke PA, Ginsberg JS, Lieberman JR, Webster AK, Whipple JP, Peters GR, Clifford W, Colwell CW Jr (2002) Ximelagatran versus Warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized double-blind trial. Ann Intern Med 137:648-655Google Scholar
  13. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Guy Paiement G, Peters GR (2003) Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 349:1703-1712PubMedCrossRefGoogle Scholar
  14. Gibert M, Sanchez-Mazas A (2003) Geographic patterns of functional categories of HLA-DRB1 alleles: a new approach to analyse associations between HLA-DRB1 and disease. Eur J Immunogenet 30:361-374PubMedCrossRefGoogle Scholar
  15. Gomez-Lechon MJ, Donato MT, Castell JV, Jover R (2003) Human hepatocytes as a tool for studying toxicity and drug metabolism. Curr Drug Metab 4:292-312PubMedCrossRefGoogle Scholar
  16. Hirsch J, Dahlen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D (2001) Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119(Suppl):8S-21SGoogle Scholar
  17. Kenne K, Skanberg I, Glinghammar B, Berson B, Pessayre D, Flinois J-P, Beaune P, Edebert I, Diaz Pohl C, Carlsson T, Andersson TB (2008) Prediction of drug induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol In Vitro 22:730-746PubMedCrossRefGoogle Scholar
  18. Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, Carlsson S, Cederbrant KE, Gibson NJ, Armstrong M, Lagerström-Fermér ME, Dellsén A, Brown EM, Thornton M, Dukes C, Jenkins SC, Firth MA, Harrod GO, Pinel THE, Billing-Clason SM, Cardon LR, March RE (2008) Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenom J 8:186-195Google Scholar
  19. Lee WM (2003) Drug-induced hepatotoxicity. N Engl J Med 349:474-485Google Scholar
  20. Lee WM, Larrey D, Olsson R, Lewis JH, Keisu M, Auclert L, Sheth S (2005) Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf 28:351-370PubMedCrossRefGoogle Scholar
  21. Lewis JH, Larrey D, Olsson R, Lee WM, Frison L, Keisu M (2008) Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of ximelagatran. Int J Clin Pharmacol Ther 46: 327-329Google Scholar
  22. Navarro VJ, Senior JR (2006) Drug-related hepatotoxicity. New Eng J Med 354:731-739PubMedCrossRefGoogle Scholar
  23. Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP (2005) The role of metabolic activation in drug-induced hepatotoxicity. Ann Rev Pharmacol Toxicol 45:177-202CrossRefGoogle Scholar
  24. Petersen P, Grind M, Adler J et al (2003) Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose guiding tolerability and safety study. J Am Coll Cardiol 41:1445-1451Google Scholar
  25. Pichler WJ (2002) Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2:301-305PubMedCrossRefGoogle Scholar
  26. Repa JJ, Mangelsdorf DJ (2000) The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Ann Rev Cell Dev Biol 16:459-481CrossRefGoogle Scholar
  27. Schulman S, Wåhlander K, Lundström T, Billing Clason S, Eriksson H for the THRIVE III Investigators (2003) Secondary prevention of venous thromboembolism with the oral direct thrombin tnhibitor ximelagatran. N Engl J Med 349:1713-1721Google Scholar
  28. SPORTIF Executive Steering Committee for the SPORTIF V Investigators (2005) Ximelagatran vs Warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. A randomized trial. JAMA 293:690-698Google Scholar
  29. Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodwin A, Nyström P, Bylock A (2003) Oral ximelagatarn for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 362:789-797PubMedCrossRefGoogle Scholar
  30. Wang H, LeCluyse EL (2003) Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokin 42:1331-1357CrossRefGoogle Scholar
  31. Wolzt M, Wollbratt M, Svensson M, Wåhlander K, Grind M, Eriksson UG (2003) Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol 59:537-543PubMedCrossRefGoogle Scholar
  32. Wolzt M, Sarich TS, Eriksson UG (2005) Pharmacokinetics and pharmacodynamics of ximelagatran. Sem Vasc Med 5:245-253CrossRefGoogle Scholar
  33. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, Lundström T, Berkowitz SD, Nyström P, Thorsén M, Ginsberg JS (2005) Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis. A randomized trial. JAMA 293:681-689Google Scholar

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.AstraZeneca, R&D Mölndal, S 431 83 Mölndal, Sweden and Section of Pharmacogenetics, Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden

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