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Drug-Induced Liver Injury Throughout the Drug Development Life Cycle: Where We Have Been, Where We are Now, and Where We are Headed. Perspectives of a Clinical Hepatologist

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Abstract

The subject of drug-induced liver injury (DILI) has been evolving for decades. While various guidance and other documents have been produced to help identify and manage DILI in the clinical trial setting, as well as the clinic, there are still many aspects of the process that remain incomplete. I have selected those aspects where guidance documents either do not cover all possible scenarios or where other recommendations are open to interpretation or where controversies still exist. The following discussion includes a number of these topics, including: when is it acceptable to continue development of a drug where hepatotoxicity is observed in animal models or other preclinical assessments? Should patients with underlying liver disease be routinely included in clinical trials? Are the current clinical and biochemical stopping rules for suspected DILI appropriate for all situations? Should we still be using fold elevations based on upper limits of normal or a subject’s own baseline values to assess the level of alanine aminotransferase or other liver-associated enzyme elevations? How can we best integrate the expanding fields of toxicogenomics, pharmacogenomics, metobolomics, proteomics and other new drug and host profiling into predicting DILI? Where do we stand with respect to a DILI biomarker to replace traditional liver associated enzymes? How do we improve upon the voluntary reporting system for adverse drug reactions? What are the most useful causality assessment methodologies to diagnose DILI and is it ever possible to exclude the drug in question? And how do we best determine and manage the competing benefits and risks of an agent causing DILI?

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References

  1. Temple R. The drug development process. An FDA perspective. In: Friedman G, Jacobson ED, McCallum RW, editors. Gastrointestinal pharmacology and therapeutics. Philadelphia: Lippincott-Raven Publishers; 1997. p. 677–92.

  2. Hutt PB. Investigations and reports respecting FDA regulations of new drugs (parts I and II). Clinical Pharmacol Ther 1983;33(4):537–48, 674–87.

    Google Scholar 

  3. Shulman SR, Hewitt T, Manocchioa M. Studies and inquiries into the FDA regulatory process: a historical review. Drug Inf J. 1995;29:385–413.

    Google Scholar 

  4. Stevens JL, Baker TK. The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov Today. 2009;14(3–4):162–7.

    PubMed  Google Scholar 

  5. Senior JR. Drug hepatotoxicity from a regulatory perspective. Clin Liver Dis. 2007;11:507–24.

    PubMed  Google Scholar 

  6. Committee on the Assessment of the US Drug Safety System. Baciu A, Stratton K, Burke SP, editors. The future of drug safety: promoting and protecting the health of the public. Washington, DC: The National Academies Press; 2007.

  7. FDA. FDA drug development and approval process. http://www.fda.gov/drugs/developmentapprovalprocess/default.htm. (Accessed 22 March 2013).

  8. FDA. Innovation or stagnation: challenges and opportunities on the critical path to new medical products (2004). http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm (Accessed 21 March 2013).

  9. Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.

  10. Popper H, Rubin E, Cardiol D, et al. Drug-induced liver disease: a penalty for progress. Arch Intern Med. 1965;115:128–36.

    CAS  PubMed  Google Scholar 

  11. Schuster D, Laggner C, Langer T. Why drugs fail—a study on side effects in new chemical entities. Curr Pharm Des. 2005;11(27):3545–59.

    CAS  PubMed  Google Scholar 

  12. Olson H. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol. 2000;32(1):56–67.

    CAS  PubMed  Google Scholar 

  13. FDA. Liver Toxicity Knowledge Base (LTKB) http://www.fda.gov/ScienceResearch/BioinformaticsTools/LiverToxicityKnowledgeBase/default.htm (Accessed 22 March 2013).

  14. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of black box warnings and withdrawals for prescription medications. JAMA. 2002;287(17):2215–20.

    PubMed  Google Scholar 

  15. FDA guidance exploratory studies FDA Working Group. Nonclinical assessment of potential hepatotoxicity in man. November 2000. http://www.fda.gov/downloads/drugs/scienceresearch/researchareas/ucm091453.pdf (Accessed 21 March 2013).

  16. Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions. Arch Intern Med. 2005;165(12):1363–9.

    PubMed  Google Scholar 

  17. Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance. Pharmacoepidemiol Drug Saf. 2001;10(5):407–10.

    CAS  PubMed  Google Scholar 

  18. Szarfman A, Machado SG, O’Neill RT. Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA’s spontaneous reports database. Drug Saf. 2002;25(6):381–92.

    CAS  PubMed  Google Scholar 

  19. Guidance for clinical trial sponsors on the establishment and operation of clinical trial data monitoring committees: draft guidance. Rockville: Food and Drug Administration; 2001. http://www.fda.gov/downloads/Regulatoryinformation/Guidances/ucm127073.pdf (Accessed 21 March 2013).

  20. Ahmad SR. Adverse drug event monitoring at the Food and Drug Administration. J Gen Intern Med. 2003;18(1):57–60.

    PubMed Central  PubMed  Google Scholar 

  21. Rosebraugh CJ, Tsong Y, Zhou F, et al. Improving the quality of adverse drug reaction reporting by 4th-year medical students. Pharmacoepidemiol Drug Saf. 2003;12(2):97–101.

    PubMed  Google Scholar 

  22. Hartford CG, Ptechel KS, Mickail H, et al. Pharmacovigilance during the pre-approval phases: an evolving pharmaceutical industry model in response to ICH E2E, CIOMS VI, FDA and EMEA/CHMP risk-management guidelines. Drug Saf. 2006;29(8):657–73.

    PubMed  Google Scholar 

  23. Cook DM, Gurugubelli RK, Bero LA. Risk management policy and black-box warnings: a qualitative analysis of US FDA proceedings. Drug Saf. 2009;32(11):1057–66.

    PubMed  Google Scholar 

  24. Grandinetti CA, Osborne SF. The Food and Drug Administration’s drug safety oversight board: an evolving paradigm for clinical input on drug safety topics. Clin Pharmacol Ther. 2010;88(2):269–74.

    CAS  PubMed  Google Scholar 

  25. Liu Z, Shi Q, Ding D, et al. Translating clinical findings into knowledge in drug safety evaluation—drug-induced liver injury prediction system (DILIps). PLoS Comput Biol. 2011;7(12):e1002310.

    Google Scholar 

  26. Behrman RE, Benner JS, Brown JS, et al. Developing the sentinel system—a national resource for evidence development. N Engl J Med. 2011;364(6):498–9.

    CAS  PubMed  Google Scholar 

  27. Platt R, Carnahan RM, Brown JS, et al. The US Food and Drug Administration’s mini-sentinel program: status and direction. Pharmacoepidemiol Drug Saf. 2012;21(suppl 1):1–8.

    PubMed  Google Scholar 

  28. Food and Drug Administration. Guidance for industry: post-marketing studies and clinical trials—implementation of section 505 (o)(3) of the federal Food, Drug, and Cosmetic Act; 2011. http://www.fda.gov/downloads/Drugs/GuidanceComlianceRegulatoryInformation/Guidances/UCM172001.pdf (Accessed 21 March 2013).

  29. Sherman RB, Woodcock J, Norden J, et al. New FDA regulation to improve safety reporting in clinical trials. N Engl J Med. 2011;365(1):3–5.

    CAS  PubMed  Google Scholar 

  30. Morrato EH, Ling SB. The Drug Safety and Risk Management Advisory Committee: a case study of meeting frequency, content, and outcomes before and after FDAAA. Med Care. 2012;50(11):970–86.

    PubMed  Google Scholar 

  31. Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15(4):241–3.

    PubMed  Google Scholar 

  32. Graham DJ, Green L, Senior JR, et al. Troglitazone-induced liver failure: a case-study. Am J Med. 2003;114(4):299–306.

    PubMed  Google Scholar 

  33. Faich GA, Moseley RH. Troglitazone (Rezulin) and hepatic injury. Pharmacoepidemiol Drug Saf. 2001;10(6):537–47.

    CAS  PubMed  Google Scholar 

  34. Fontana RJ, McCashland TM, Brenner KG, et al. Acute liver failure associated with prolonged use of bromfenac leading to liver transplant. Liver Transpl Surg. 1999;5(6):480–4.

    CAS  PubMed  Google Scholar 

  35. Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol Drug Saf. 2006;15.

  36. Tancik CA, Dillaha JA. Trovafloxacin-induced acute hepatitis. Clin Infect Dis. 2000;30(2):400.

    Google Scholar 

  37. FDA Working Group (Temple R, Senior JR). Clinical white paper, 2000. Conference on drug-induced liver injury: a national and global problem. Chantilly; 2001. http://www.fda.gov/cder/livertox/clinical.pdf.

  38. Guidance for industry. Drug-induced liver injury: premarketing clinical evaluation. Food and Drug Administration, Silver Spring; 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf (Accessed 21 March 2013).

  39. Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology. 2006;43(3):618–31.

    PubMed  Google Scholar 

  40. Reuben A, Koch DG, Lee WM, et al. Drug-induced acute liver failure: results of a US multicenter, prospective study. Hepatology. 2010;52(6):2065–76.

    PubMed  Google Scholar 

  41. Hoofnagle JH, Serrano J, Knoben JE, et al. Liver Tox. A web site on drug induced liver injury. Hepatology. 2013;57(3):873–4.

    PubMed  Google Scholar 

  42. Lewis JH, Kleiner DE. Hepatic injury due to drugs, herbal compounds, chemicals and toxins. In: Burt AD, Portmann BC, Ferrell LD, editors. MacSween’s pathology of the liver. 6th ed. Edinburgh: Churchill Livingstone/Elsevier; 2012. p. 645–760.

    Google Scholar 

  43. Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol. 2007;102(3):558–62.

    PubMed  Google Scholar 

  44. Mindikoglu AL, Magder LS, Regev A. Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the United Network for Organ Sharing database. Liver Transpl. 2009;15(7):719–29.

    PubMed  Google Scholar 

  45. Lee WM. Assessing causality in drug-induced liver injury. J Hepatol. 2000;33(6):1003–5.

    CAS  PubMed  Google Scholar 

  46. Goodman Z. Drug hepatotoxicity. Clin Liver Dis. 2002;6(2):381–9.

    PubMed  Google Scholar 

  47. Kaplowitz N. Drug-induced liver disorders: implications for drug development and regulation. Drug Saf. 2001;24(7):483–90.

    CAS  PubMed  Google Scholar 

  48. Kleiner DE. The pathology of drug-induced liver injury. Semin Liver Dis. 2009;29(4):364–72.

    PubMed  Google Scholar 

  49. Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century-Crofts; 1978.

    Google Scholar 

  50. Benichou C, Benhamou JP, Danan G. Consensus. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272–6.

    CAS  PubMed  Google Scholar 

  51. Benichou C. Standardization of definitions and criteria of causality assessment of adverse drug reactions. Drug-induced liver disorders: report of an international consensus meeting. Int J Clin Pharmacol Ther Toxicol. 1990;28(8):317–22.

    Google Scholar 

  52. Senior JR. How can “Hy’s law” help the clinician? Pharmacoepidemiol Drug Saf. 2006;15(4):235–9.

    PubMed  Google Scholar 

  53. West M, Gelb D, Pilz CG, Zimmerman HJ. Serum enzymes in disease. VII. Significance of abnormal serum enzyme levels in cardiac failure. Am J Med Sci. 1961;241:350–8.

    CAS  PubMed  Google Scholar 

  54. West M, Heller P, Zimmerman HJ. Serum enzymes in disease. III. Lactic dehydrogenase and glutamic oxaloacetic transaminase in patients with leukemia and lymphoma. Am J Med Sci. 1958;235(6):689–701.

    CAS  PubMed  Google Scholar 

  55. West M, Zimmerman HJ. Lactic dehydrogenase and glutamic oxaloacetic transaminase in normal pregnant women and newborn children. Am J Med Sci. 1958;235(4):443–7.

    CAS  PubMed  Google Scholar 

  56. Korn RJ, Rock W, Zimmerman HJ. Studies of hepatic function in patients receiving promazine. Am J Med Sci. 1958;235(4):431–6.

    CAS  PubMed  Google Scholar 

  57. Dujovne CA, Levy R, Zimmerman HJ. Hepatotoxicity of phenothiazines in vitro as measured by loss of aminotransferases to surrounding media. Proc Soc Exp Biol Med. 1968;128(2):561–3.

    CAS  PubMed  Google Scholar 

  58. Senior JR. Monitoring for hepatotoxicity: what is the predictive value of liver ‘function’ tests? Clin Pharmacol Ther. 2009;85(3):331–4.

    CAS  PubMed  Google Scholar 

  59. American Gastroenterological Association position statement: evaluation of liver chemistry tests. Gastroenterology. 2002;123(4):1364–6.

    Google Scholar 

  60. Green RM, Flamm S. AGA Technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002;123(4):1367–84.

    PubMed  Google Scholar 

  61. Nathwani RA, Pais S, Reynolds TB, et al. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology. 2005;41(2):380–2.

    CAS  PubMed  Google Scholar 

  62. Mohi-ud-din R, Lewis JH. Drug- and chemical-induced cholestasis. Clin Liver Dis. 2004;8(1):95–132.

    PubMed  Google Scholar 

  63. Wolkoff AW, Berk PD. Bilirubin metabolism and jaundice. In: Schiff ER, Maddrey WC, Sorredll MF, editors. Schiff’s diseases of the liver. 11th ed. New York: Wiley-Blackwell; 2012. p. 120–51.

  64. Hawkins MT, Lewis JH. Latest advances in predicting DILI in human subjects: focus on biomarkers. Expert Opin Drug Metab Toxicol. 2012;8(12):1521–30.

    CAS  PubMed  Google Scholar 

  65. Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation and pathogenesis. Am J Med. 2000;109(2):109–13.

    CAS  PubMed  Google Scholar 

  66. Henrion J, Schapira M, Luwaert R, et al. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore). 2003;82(6):392–406.

    Google Scholar 

  67. Harinasuta U, Chomet B, Ishak K, et al. Steatonecrosis—Mallory body type. Medicine (Baltimore). 1967;46(2):141–62.

    CAS  Google Scholar 

  68. Vuppalanchi R, Hayashi PH, Chalasani N, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther. 2010;32(9):1174–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Bissell DM, Gores GJ, Laskin DL, et al. Drug-induced liver injury—mechanisms and test systems. Hepatology. 2001;33(4):1009–13.

    CAS  PubMed  Google Scholar 

  70. Kaplowitz M. Idiosyncratic drug hepatotoxicity. Nature Rev Drug Discov. 2005;4:489–9.

    Google Scholar 

  71. Gunawan VK, Kaplowitz N. Mechanisms of drug-induced liver disease. Clin Liver Dis. 2007;11(3):459–75.

    PubMed  Google Scholar 

  72. Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474–85.

    CAS  PubMed  Google Scholar 

  73. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.

    CAS  PubMed  Google Scholar 

  74. Trauner M, Meier PJ, Boyer JL. Molecular basis of cholestasis. N Engl J Med. 1998;339(17):1217–27.

    CAS  PubMed  Google Scholar 

  75. Metushi IG, Cai P, Zhu X, et al. A fresh look at the mechanism of isoniazid-induced hepatotoxicity. Clin Pharmacol Ther. 2011;89(6):911–4.

    CAS  PubMed  Google Scholar 

  76. Verma S, Kaplowitz N. Diagnosis, management, and prevention of drug-induced liver injury. Gut. 2009;58(11):1555–64.

    CAS  PubMed  Google Scholar 

  77. Lewis JH. Drug-induced liver disease. Med Clin North Am. 2000;84(5):1275–311.

    CAS  PubMed  Google Scholar 

  78. Lucena M, Andrade R, Kaplowitz N, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology. 2009;49(6):2001–9.

    PubMed  Google Scholar 

  79. Jones DP, Lemasters JJ, Han D, et al. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Interv. 2010;10(2):98–111.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Boelsterli UA, Lim PL. Mitochondrial abnormalities—a link to idiosyncratic drug hepatotoxicity? Toxicol Appl Pharmacol. 2007;220(1):92–107.

    CAS  PubMed  Google Scholar 

  81. Uetrecht J. Role of drug metabolism for breaking tolerance and the localization of drug hypersensitivity. Toxicology. 2005;209(2):113–8.

    CAS  PubMed  Google Scholar 

  82. Han D, Shinohara M, Ybanez MD, et al. Signal transduction pathways involved in drug-induced liver injury. Handb Exp Pharmacol. 2010;196:267–310.

    CAS  PubMed  Google Scholar 

  83. Amacher DE. The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2012;8(3):335–47.

    CAS  PubMed  Google Scholar 

  84. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Semin Liver Dis. 2009;29(4):400–11.

    CAS  PubMed  Google Scholar 

  85. Daly AK. Drug-induced liver injury: past, present, and future. Pharmacogenomics. 2010;5:607–11.

    Google Scholar 

  86. Daly ASK, Day CP. Genetic association studies in drug-induced liver injury. Drug Metab Rev. 2012;44(1):116–26.

    CAS  PubMed  Google Scholar 

  87. Uetrecht J. Immunoallergic drug-induced liver injury in humans. Semin Liver Dis. 2009;29(4):383–92.

    CAS  PubMed  Google Scholar 

  88. Lammert C, Einarsson S, Saha C, et al. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47(6):2003–9.

    CAS  PubMed  Google Scholar 

  89. Lammert C, Bjornsson E, Niklasson A, et al. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse effects. Hepatology. 2010;51(2):615–20.

    CAS  PubMed  Google Scholar 

  90. Ng W, Lobach AR, Zhu X, et al. Animal models of idiosyncratic drug reactions. Adv Pharmacol. 2012;63:81–135.

    CAS  PubMed  Google Scholar 

  91. Corsini A, Ganey P, Ju C, et al. Current challenges and controversies in drug-induced liver injury. Drug Saf. 2012;35(12):1099–117.

    CAS  PubMed  Google Scholar 

  92. Zhang M, Chen M, Tong W. Is toxicogenomics a more reliable and sensitive biomarker than conventional indicators from rats to predict drug-induced injury in humans. Chem Res Toxicol. 2012;25(1):122–9.

    CAS  PubMed  Google Scholar 

  93. Horsmans Y, Desager JP, Harvengt C. Biochemical changes and morphological alterations of the liver in guinea-pigs after administration of simvastatin (HMG CoA reductase-inhibitor). Pharmacol Toxicol. 1990;67(4):336–9.

    CAS  PubMed  Google Scholar 

  94. Kornbrust DJ, MacDonald JS, Peter CP, et al. Toxicity of HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits. J Pharmacol Exp Ther. 1989;248(2):498–505.

    CAS  PubMed  Google Scholar 

  95. Lewis JH. Clinical perspective: statins and the liver—harmful or helpful? Dig Dis Sci. 2012;57(7):1754–63.

    PubMed  Google Scholar 

  96. Holsapple MP, Pitot HC, Cohen SH, et al. Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol Sci. 2006;89(1):51–6.

    CAS  PubMed  Google Scholar 

  97. Uetrecht J. Role of animal models in the study of drug-induced hypersensitivity reactions. AAPS J. 2006;7(4):E914–21.

    PubMed Central  PubMed  Google Scholar 

  98. Dixit R, Boelsterli UA. Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discov Today. 2007;12(7–8):336–42.

    CAS  PubMed  Google Scholar 

  99. Food and Drug Administration. Guidance for Industry, Investigations and reviewers. Exploratory IND studies; 2006. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf (Accessed 21 March 2013).

  100. Ballet F. Hepatotoxicity in drug development: detection, significance and solutions. J Hepatol. 1997;26(suppl 2):26–36.

    CAS  PubMed  Google Scholar 

  101. Abernethy DR, Woodcock J, Lesko LJ. Pharmacological mechanism-based drug safety assessment and prediction. Clin Pharmacol Ther. 2011;89(6):793–7.

    CAS  PubMed  Google Scholar 

  102. Ikeda T. Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case. Drug Metab Pharmacokinet. 2011;26(1):60–70.

    CAS  PubMed  Google Scholar 

  103. Amacher DE. The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity. Toxicol Appl Pharmacol. 2010;245(1):134–42.

    CAS  PubMed  Google Scholar 

  104. Cheng F, Theodorescu D, Shulman I, Lee J. In vitro transcriptomic prediction of hepatotoxicity for early drug discovery. J Theoret Biol. 2011;290:27–36.

    CAS  Google Scholar 

  105. O’Connell TM, Watkins PB. The application of metabonomics to predict drug-induced liver injury. Clin Pharmacol Ther. 2010;88(3):394–9.

    PubMed  Google Scholar 

  106. Waters NJ. The role of metabonomics at the interface between drug metabolism and safety assessment. Curr Drug Metab. 2010;11(8):686–92.

    CAS  PubMed  Google Scholar 

  107. Mandenius C, Andersson T, Alves P, et al. Toward preclinical predictive drug testing for metabolism and hepatotoxicity by using in vitro models derived from human embryonic stem cells and human cell lines—a report of the Vitrocellomics EU-project. Altern Lab Anim. 2011;39(2):147–71.

    CAS  PubMed  Google Scholar 

  108. Van Summeren A, Renes J, van Delft J, et al. Proteomics in the search for mechanisms and biomarkers of drug-induced hepatotoxicity. Toxicol In Vitro. 2012;26(3):373–85.

    PubMed  Google Scholar 

  109. Kia R, Sison RL, Heslop J, et al. Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury: are we there yet? Br J Clin Pharmacol. 2013;75(4):885–96.

    PubMed  Google Scholar 

  110. Low Y, Uehara T, Minowa Y, et al. Predicting drug-induced hepatotoxicity using QSAR and toxigenomics approaches. Chem Res Toxicol. 2011;24(8):1251–62.

    CAS  PubMed  Google Scholar 

  111. Ebbels TM, Keun HC, Beckonert OP, et al. Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach. J Proteosome Res. 2007;6(11):4407–22.

    CAS  Google Scholar 

  112. Przybylak KR, Cronin MT. In silico models for drug-induced liver injury—current status. Expert Opin Drug Metab Toxicol. 2012;8(2):201–17.

    CAS  PubMed  Google Scholar 

  113. McBurney RN, Hines W, Von Tungelin LS, et al. The liver toxicity biomarker study: phase design and preliminary results. Toxicol Pathol. 2009;37(1):52–64.

    CAS  PubMed  Google Scholar 

  114. Stepan A, Walker D, Bauman J, Price D, et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the Unites States. Chem Res Toxicol. 2011;24(9):1345–410.

    CAS  PubMed  Google Scholar 

  115. Kalgutkar AS, Didiuk MT. Structural alerts, reactive metabolites, and protein covalent binding: how reliable are these attributes as predictors of drug toxicity? Chem Biodivers. 2009;6(11):2115–37.

    CAS  PubMed  Google Scholar 

  116. Gonzalbes R, Pineda-Lucena A. Small molecule databases and chemical descriptors useful in chemoinformatics: an overview. Comb Chem Throughput Screen. 2011;14(6):548.

    Google Scholar 

  117. Shi Q, Hong H, Senior J, et al. Biomarkers for drug-induced liver injury. Expert Rev Gastroenterol Hepatol. 2010;4(2):225–34.

    CAS  PubMed  Google Scholar 

  118. Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov. 2012;11(10):751–61.

    CAS  PubMed  Google Scholar 

  119. Valentin JP, Bialecki R, Ewart L, et al. A framework to assess the translation of safety pharmacology data to humans. J Pharmacol Toxicol Methods. 2009;60(2):152–8.

    CAS  PubMed  Google Scholar 

  120. Watkins PB. Drug safety sciences and the bottleneck in drug development. Clin Pharmacol Ther. 2011;89(6):788–90.

    CAS  PubMed  Google Scholar 

  121. Reuben A. Hy’s law. Hepatology. 2004;39(2):574–8.

    PubMed  Google Scholar 

  122. Davidson CS, Leevy CM, Chamberlayne EC (eds). Guidelines for evaluation of potential hepatotoxicity of drugs in clinical trials, chapter 8. In: Guidelines for detection of hepatotoxicity due to drugs and chemicals [Fogary Conference]. NIH, USA. Publication No 79-313; 1978. p. 106–18.

  123. Lewis JH. ‘Hy’s law’, ‘the Rezulin Rule’ and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective. Pharmacoepidemiol Drug Saf. 2006;15(4):221–9.

    CAS  PubMed  Google Scholar 

  124. Kaplowitz N. Rules and laws of drug hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15(4):231–3.

    CAS  PubMed  Google Scholar 

  125. Andrade RL, Lucena MI, Fernandez MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129(2):512–21.

    PubMed  Google Scholar 

  126. Bjornsson E, Olsson R. Outcome and prognostic markers to severe drug-induced liver disease. Hepatology. 2005;42(2):481–9.

    PubMed  Google Scholar 

  127. Chalasani N, Fontana RJ, Bonjovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135(6):1924–34.

    PubMed Central  PubMed  Google Scholar 

  128. Devarbhavi H, Dierkhising R, Kremers W, et al. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010;105(11):2396–404.

    PubMed  Google Scholar 

  129. Marino G, Zimmerman HJ, Lewis JH. Management of drug-induced liver disease. Curr Gastroenterol Rep. 2001;3(1):38–48.

    CAS  PubMed  Google Scholar 

  130. Guo T, Gelperin K, Senior JR. A tool to help you decide (detect potentially serious liver injury). http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm076777.pdf (Accessed 21 March 2013).

  131. Llanos L, Moreu R, Ortin T, et al. The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports. Aliment Pharmacol Ther. 2010;31(12):1337–45.

    CAS  PubMed  Google Scholar 

  132. Lee WM, Larrey D, Olsson R, et al. Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf. 2005;28(4):351–70.

    CAS  PubMed  Google Scholar 

  133. Andrade RJ, Lucena MI, Martin-Vivaldi R, et al. Acute liver injury associated with the use of ebrotidine, a new H2-receptor antagonist. J Hepatol. 1999;31(4):641–6.

    CAS  PubMed  Google Scholar 

  134. Singer JB, Lewitzky S, Leroy E, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 2010;42(8):711–1471.

    CAS  PubMed  Google Scholar 

  135. Sotaxatan Thelin (sitaxentan) to be withdrawn due to cases of unpredictable serious liver injury—clinical trials are also to be stopped. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/12/WC500099707.pdf (Accessed 21 March 2013).

  136. Eypasch E, Leferinga R, Kuma CK, et al. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ. 1995;311:619.

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Lin X, Parks D, Painter J, et al. Validation of multivariate outlier detection analyses used to identify potential drug-induced liver injury in clinical trial populations. Drug Saf. 2012;35(10):865–75.

    PubMed  Google Scholar 

  138. Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf. 2011;34(3):243–52.

    PubMed  Google Scholar 

  139. Morris M, Lane P, Lee K, et al. An integrated analysis of liver safety data from orlistat clinical trials. Obes Facts. 2012;5(4):485–94.

    PubMed  Google Scholar 

  140. Lewis JH. The adaptive response (drug tolerance) helps prevent drug-induced liver disease. Gastroenterol Hepatol. 2012;8(5):333–6.

    Google Scholar 

  141. Adams DH, Ju C, Ramaiah SK, et al. Mechanisms of immune-mediated liver injury. Toxicol Sci. 2010;115(2):307–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Bourdi M, Eiras DP, Holt MP, et al. Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury. Chem Res Toxicol. 2007;20(2):208–16.

    CAS  PubMed  Google Scholar 

  143. Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994;271(13):992–8.

    CAS  PubMed  Google Scholar 

  144. Watkins PB, Dube LM, Walton-Bowen K, et al. Clinical pattern of zileuton-associated liver injury: results of a 12-month study in patients with chronic asthma. Drug Saf. 2007;30(9):805–15.

    CAS  PubMed  Google Scholar 

  145. Leaver H, Keng Lim T, Thompson P, et al. Compliance to recommended liver function monitoring in patients on statin therapy. Cardiovasc Ther. 2009;27(2):96–100.

    PubMed  Google Scholar 

  146. Bader T. The myth of statin-induced hepatotoxicity. Am J Gastroenterol. 2010;105(5):978–80.

    PubMed  Google Scholar 

  147. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm (Accessed 21 March 2013).

  148. Graham D, Drinkard C, Shatin D, Tsong Y, et al. Liver enzyme monitoring in patients treated with troglitazone. JAMA. 2001;286(7):831–3.

    CAS  PubMed  Google Scholar 

  149. Okie S. Safety in numbers—monitoring risk in approved drugs. N Engl J Med. 2005;352(12):1173–6.

    CAS  PubMed  Google Scholar 

  150. Phillips E, Mallal S. Successful translation of pharmacogenetics into the clinic: the abacavir example. Mol Diagn Ther. 2009;13(1):1–9.

    PubMed  Google Scholar 

  151. Gupta N, Lewis JH. Review article: The use of potentially hepatotoxic drugs in patients with liver disease. Aliment Pharmacol Ther. 2008;28(9):1021–41.

    CAS  PubMed  Google Scholar 

  152. FDA Guidance for industry. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. Food and Drug Administration; 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf (Accessed 21 March 2013).

  153. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf (Accessed 21 March 2013).

  154. Lewis JH, Mortensen ME, Zweig S, et al. Safety and efficacy of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease. Results of a prospective, randomized, double-blind, placebo-controlled trial. Hepatology. 2007;46(5):1453–63.

    CAS  PubMed  Google Scholar 

  155. M’Kada H, Munteanu M, Perazzo H, et al. What are the best reference values for a normal serum alanine transaminase activity (ALT)? Impact on the presumed prevalence of drug induced liver injury (DILI). Regul Toxicol Pharmacol. 2011;60(3):290–5.

    PubMed  Google Scholar 

  156. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–10.

    CAS  PubMed  Google Scholar 

  157. Zheng MH, Shi KQ, Fan YC, et al. Upper limits of normal for serum alanine aminotransferase levels in Chinese Han population. PLoS One. 2012;7(9):e43736.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Elinav E, Ben-Dov IZ, Ackerman E, et al. Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern. Am J Gastroenterol. 2005;100(10):2201–4.

    PubMed  Google Scholar 

  159. Dong MH, Bettencourt R, Brenner DA, et al. Serum levels of alanine aminotransferase decrease with age in longitudinal analysis. Clin Gastroenterol Hepatol. 2012;10(3):285–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Watkins PB, Merz M. Liver safety assessment in clinical drug development: best practices workshop. Boston: Hilton Back Bay Hotel; 2012.

  161. Lee WM, Senior JR. Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol. 2005;33(1):155–64.

    CAS  PubMed  Google Scholar 

  162. Aithal GP, Rawlins MD, Day CP. Accuracy of hepatic adverse drug reaction reporting in one English health region. BMJ. 1999;319(11):1541.

    Google Scholar 

  163. Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology. 2001;33(1):308–10.

    CAS  PubMed  Google Scholar 

  164. Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30.

    CAS  PubMed  Google Scholar 

  165. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46(11):1331–6.

    CAS  PubMed  Google Scholar 

  166. Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol. 2000;33(6):949–52.

    CAS  PubMed  Google Scholar 

  167. Maria VAJ, Victorino RMM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology. 1997;26(3):664–9.

    CAS  PubMed  Google Scholar 

  168. Lucena M, Camargo R, Andrade R, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 2001;33(1):123–30.

    CAS  PubMed  Google Scholar 

  169. Shapiro M, Lewis JH. Causality assessment of drug-induced liver disease. Promises and pitfalls. Clin Liver Dis. 2007;11(3):477–505.

    PubMed  Google Scholar 

  170. Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–15.

    CAS  PubMed  Google Scholar 

  171. Blanc S, Leuenberger P, Berger J-P, et al. Judgments of trained observers on adverse drug reactions. Clin Pharmacol Ther. 1979;25(5):493–8.

    CAS  PubMed  Google Scholar 

  172. Teschke R, Schulze J. Suspected herbal hepatotoxicity: requirements for appropriate causality assessment by the US Pharmacopeia. Drug Saf. 2012;35(12):1091–7.

    PubMed  Google Scholar 

  173. Lewis JH, Larrey D, Olsson R, et al. Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran. Int J Clin Pharmacol Ther. 2008;46(7):327–39.

    CAS  PubMed  Google Scholar 

  174. Rockey DC, Seeff LB, Rochon J, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf Causality Assessment Method. Hepatology. 2010;51(6):2117–26.

    PubMed Central  PubMed  Google Scholar 

  175. Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology. 2010;52(2):737–42.

    Google Scholar 

  176. Nathwani RA, Kumar SR, Reynolds TB, et al. Marked elevation in serum transaminases: an atypical presentation of choledocholithiasis. Am J Gastroenterol. 2005;100(2):295–8.

    CAS  PubMed  Google Scholar 

  177. Barritt AS 4th, Lee J, Hayashi PH. Detective work in drug-induced liver injury: sometimes it is all about interviewing the right witness. Clin Gastroenterol Hepatol. 2010;8(7):635–7.

    PubMed Central  PubMed  Google Scholar 

  178. Hoofnagle JH, Hepatitis E. N Engl J Med. 2012;367(13):1237–44.

    CAS  PubMed  Google Scholar 

  179. Dalton HR, Fellows HJ, Stableforth W, et al. The role of hepatitis E virus testing in drug-induced liver injury. Aliment Pharmacol Ther. 2007;26(10):1429–35.

    CAS  PubMed  Google Scholar 

  180. Davern TJ, Chalasani N, Fontana RJ, et al. Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology. 2011;141(5):1665–72.

    PubMed Central  PubMed  Google Scholar 

  181. Chen EY, Baum K, Collins W, et al. Hepatitis E masquerading as drug-induced liver injury. Hepatology. 2012;56(6):2420–3.

    PubMed  Google Scholar 

  182. Watkins PB, Seligman PJ, Pears JS, et al. Using controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology. 2008;48(5):1680–9.

    PubMed  Google Scholar 

  183. Little RJ, D’Agostino R, Cohen ML, et al. The prevention and treatment of missing clinical data in clinical trials. N Engl J Med. 2012;367(14):1355–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Agarwal VK, McHutchison JG, Hoofnagle JH, for the Drug-induced Liver Injury Network. Important elements for the diagnosis of drug-induced liver injury. Clin Gastroenterol Hepatol. 2010;8(5):463–70.

    PubMed Central  PubMed  Google Scholar 

  185. Haller C, James LP. Adverse drug reactions: moving from chance to science. Clin Pharmacol Ther. 2011;89(6):761–4.

    CAS  PubMed  Google Scholar 

  186. Brown EG. Using MedDRA: implications for risk management. Drug Saf. 2004;27(8):591–602.

    PubMed  Google Scholar 

  187. Lee WM. Acute liver failure. Semin Respir Crit Care Med. 2012;33(1):36–45.

    PubMed  Google Scholar 

  188. Allan MC. A primer of drug safety surveillance: an industry perspective. Part III: managing adverse-event data. J Pharm Technol. 1992;8(6):259–73.

    CAS  PubMed  Google Scholar 

  189. Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications. Drug Saf. 2004;27(8):509–17.

    PubMed  Google Scholar 

  190. Hammond IW, Gibbs TG, Seifert HA, et al. Database size and power to detect safety signals in pharmacovigilance. Expert Opin Drug Saf. 2007;6(6):713–21.

    CAS  PubMed  Google Scholar 

  191. Bate A, Lindquist M, Edwards IR. The application of knowledge discovery in databases to post-marketing drug safety: example of the WHO database. Fundam Clin Pharmacol. 2008;22(2):127–40.

    CAS  PubMed  Google Scholar 

  192. Giezen TJ, Mantel-Teeuwisse AK, Leufkens HG. Pharmacovigilance of biopharmaceuticals: challenges remain. Drug Saf. 2009;32(10):811–7.

    PubMed  Google Scholar 

  193. Chen M, Vijay V, Shi Q, et al. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today. 2011;16(15–16):697–703.

    PubMed  Google Scholar 

  194. Johann-Liang R, Wyeth J, Chen M, et al. Pediatric drug surveillance and the Food and Drug Administration’s adverse event reporting system: an overview of reports, 2003–2007. Pharmacoepidemiol Drug Saf. 2009;18(1):24–7.

    PubMed  Google Scholar 

  195. Hauben M, Horn S, Reich L. Potential use of data-mining algorithms for the detection of ‘surprise’ adverse drug reactions. Drug Saf. 2007;30(2):143–55.

    PubMed  Google Scholar 

  196. Rosati K. Using electronic health information for pharmacovigilance: the promise and the pitfalls. J Health Life Sci Law. 2009;2:173–239.

    Google Scholar 

  197. Avorn J. Two centuries of assessing drug risks. N Engl J Med. 2012;367(3):193–7.

    CAS  PubMed  Google Scholar 

  198. Brewster W, Gibbs T, Lacroix K, et al. Evolving paradigms in pharmacovigilance. Curr Drug Saf. 2006;1(2):127–34.

    PubMed  Google Scholar 

  199. Almenoff JS, Pattishall EN, Gibbs TG, et al. Novel statistical tools for monitoring the safety of marketed drugs. Clin Pharmacol Ther. 2007;82(2):157–66.

    CAS  PubMed  Google Scholar 

  200. Wilson AM, Thabane L, Holbrook A. Application of data mining techniques in pharmacovigilance. Br J Clin Pharmacol. 2004;57(2):127–34.

    PubMed Central  PubMed  Google Scholar 

  201. Wang HW, Hochberg AM, Pearson RK, et al. An experimental investigation of masking in the US FDA adverse event reporting system database. Drug Saf. 2010;33(12):1117–33.

    PubMed  Google Scholar 

  202. Hauben M, Reich L. Safety related drug-labelling changes: findings from two data mining algorithms. Drug Saf. 2004;27(10):735–44.

    PubMed  Google Scholar 

  203. Manso G, Thole Z, Salgueiro E, et al. Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiol Drug Saf. 2006;15(4):253–9.

    CAS  PubMed  Google Scholar 

  204. Dore DD, DiBello JR, Lapane KL. Telithromycin use and spontaneous reports of hepatotoxicity. Drug Saf. 2007;30(8):697–703.

    PubMed  Google Scholar 

  205. Chen Y, Guo JJ, Healy DP, et al. Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms. Ann Pharmacother. 2008;42(12):1791–6.

    CAS  PubMed  Google Scholar 

  206. Brinker AD, Wassel RT, Lyndly J, et al. Telithromycin-associated hepatotoxicity: clinical spectrum and causality assessment of 42 cases. Hepatology. 2009;49(1):250–7.

    PubMed  Google Scholar 

  207. Lawrenson RA, Seaman HE, Sundstrom A, et al. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf. 2000;23(4):333–49.

    CAS  PubMed  Google Scholar 

  208. Safer DJ, Zito JM, Gardner JE. Pemoline hepatotoxicity and postmarketing surveillance. J Am Acad Child Adolesc Psychiatry. 2001;40(6):622–9.

    CAS  PubMed  Google Scholar 

  209. Etwel FA, Rieder MJ, Bend JR, et al. A surveillance method for the early identification of idiosyncratic adverse drug reactions. Drug Saf. 2008;31(2):169–80.

    CAS  PubMed  Google Scholar 

  210. Conforti A, Magro L, Moretti U, et al. Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy. Drug Saf. 2006;29(12):1163–72.

    CAS  PubMed  Google Scholar 

  211. Bezabeh S, Flowers CM, Kortepeter C, et al. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31(9):1028–35.

    CAS  PubMed  Google Scholar 

  212. Hauben M, Vegni F, Reich L, et al. Postmarketing hepatic adverse event experience with PEGylated/non-PEGylated drugs: a disproportionality analysis. Eur J Gastroenterol Hepatol. 2007;19(11):934–41.

    PubMed  Google Scholar 

  213. Stromborn I, Wernicke JF, Seeger J, et al. Hepatic effects of duloxetine—III: analysis of hepatic events using external data sources. Curr Drug Saf. 2008;3(2):154–62.

    Google Scholar 

  214. Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol. 2007;99(3):379–81.

    CAS  PubMed  Google Scholar 

  215. Thiessard F, Roux E, Miremont-Salame G, et al. Trends in spontaneous adverse drug reaction reports to the French pharmacovigilance system (1986–2001). Drug Saf. 2005;28(8):731–40.

    PubMed  Google Scholar 

  216. Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to the Food and Drug Administration, 1998–2005. Arch Intern Med. 2007;167(16):1752–9.

    PubMed  Google Scholar 

  217. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2009;32(1):19–31.

    CAS  PubMed  Google Scholar 

  218. Shetty KD, Dalal SR. Using information mining of the medical literature to improve drug safety. J Am Med Inf Assoc. 2011;18(5):668–74.

    Google Scholar 

  219. Alves C, Batel-Marques F, Macedo AF. Data sources on drug safety evaluation: a review of recent published meta-analyses. Pharmacoepidemiol Drug Saf. 2012;21(1):21–33.

    PubMed  Google Scholar 

  220. Jinjuvadia K, Kwan W, Fontana RJ. Searching for a needle in a hatstack: use of ICD-9-CM codes in drug-induced liver injury. Am J Gastroenterol. 2007;102(11):2437–43.

    PubMed  Google Scholar 

  221. Sgro C, Clinard F, Quazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36(2):451–5.

    PubMed  Google Scholar 

  222. Hammond IW, Rich DS, Gibbs TG. Effect of consumer reporting on signal detection: using disproportionality analysis. Expert Opin Drug Saf. 2007;6(6):705–12.

    PubMed  Google Scholar 

  223. Basch E, Jia X, Heller G, et al. Adverse symptom reporting by patients versus clinicians: relationships with clinical outcomes. J Natl Cancer Inst. 2009;101(23):1624–32.

    PubMed Central  PubMed  Google Scholar 

  224. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362(10):865–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  225. Anderson C, Krska J, Murphy E, et al. The importance of direct patient reporting of suspected adverse drug reactions: a patient perspective. Br J Clin Pharmacol. 2011;72(5):806–22.

    PubMed Central  PubMed  Google Scholar 

  226. Avery AJ, Anderson C, Bond CM, et al. Evaluation of patient reporting of adverse drug reactions to the UK ‘Yellow Card Scheme’: literature review, descriptive and qualitative analyses, and questionnaire surveys. Health Technol Assess. 2011;15:1–234.

    CAS  PubMed  Google Scholar 

  227. Pushkin R, Frassetto L, Tsourounis C, et al. Improving the reporting of adverse drug reactions in the hospital setting. Postgrad Med. 2010;122(6):154–64.

    PubMed  Google Scholar 

  228. Gavaza P, Brown CM, Lawson KA, et al. Influence of attitudes on pharmacists’ intention to report serious adverse drug events to the Food and Drug Administration. Br J Clin Pharmacol. 2011;72(1):143–52.

    PubMed Central  PubMed  Google Scholar 

  229. Hasford J, Goettler M, Munter KH, et al. Physicians’ knowledge and attitudes regarding the spontaneous reporting system for adverse drug reactions. J Clin Epidemiol. 2002;55(9):945–50.

    CAS  PubMed  Google Scholar 

  230. Kaufman MB, Stoukides CA, Campbell NA. Physicians’ liability for adverse drug reactions. South Med J. 1994;87(8):780–4.

    CAS  PubMed  Google Scholar 

  231. Kesselheim AS, Avorn J. The role of litigation in defining drug risks. JAMA. 2007;297(3):308–11.

    CAS  PubMed  Google Scholar 

  232. Adebayo D, Mookerjee RP, Jalan R. Mechanistic biomarkers in acute liver injury: are we there yet? J Hepatol. 2012;56(5):1003–5.

    PubMed  Google Scholar 

  233. Watkins PB. Biomarkers for the diagnosis and management of drug-induced liver injury. Semin Liver Dis. 2009;29(4):393–9.

    CAS  PubMed  Google Scholar 

  234. Collins BC, Miller CA, Sposny A, et al. Development of a pharmaceutical hepatotoxicity biomarker panel using a discovery to targeted proteomics approach. Mol Cell Proteomics. 2012;11(8):394–410.

    PubMed Central  PubMed  Google Scholar 

  235. Ozer J, Ratner M, Shaw M, et al. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008;245(3):194–205.

    CAS  PubMed  Google Scholar 

  236. Ozer JS, Chetty R, Kenna G, et al. Recommendations to qualify biomarker candidates of drug-induced liver injury. Biomark Med. 2010;4(3):475–83.

    CAS  PubMed  Google Scholar 

  237. Bell LN, Vuppalanchi R, Watkins PB, et al. Serum proteomic profiling in patients with drug-induced liver injury. Aliment Pharmacol Ther. 2012;35(5):600–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  238. Abacavir. LiverTox Drug record. http://livertox.nih.gov/Abacavir.htm (Accessed 22 March 2013).

  239. Hughes DA, Vilar FJ, Ward CC, et al. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics. 2004;14(6):335–42.

    PubMed  Google Scholar 

  240. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79.

    PubMed  Google Scholar 

  241. Lucena M, Molokhia M, Shen Y. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  242. Krawczyk M, Mullenbach R, Weber S, et al. Genome-wide association studies and genetic risk assessment of liver diseases. Nat Rev Gastroenterol Hepatol. 2010;7:669–80.

    PubMed  Google Scholar 

  243. Liss G, Rattan S, Lewis JH. Predicting and preventing acute drug-induced liver injury: what’s new in 2010. Expert Opin Drug Metab Toxicol. 2010;6(9):1–15.

    Google Scholar 

  244. Stine JG, Lewis JH. Drug-induced liver injury: a summary of recent advances. Expert Opin Drug metab Toxicol. 2011;7(7):875–90.

    PubMed  Google Scholar 

  245. Pirmohamed M, Aithal GP, Behr E, et al. The phenotype standardization project: improving pharmacogenetic studies of serious adverse drug reactions. Clin Pharmacol Ther. 2011;89(6):784–8.

    CAS  PubMed  Google Scholar 

  246. Slutsky AS, Lavery JV. Data safety monitoring boards. N Engl J Med. 2004;350(11):1143–6.

    CAS  PubMed  Google Scholar 

  247. Tereskerz PM, Guterbock TM, Kermer DA, et al. An opinion and practice survey on the structure and management of data and safety monitoring boards. Acc Res. 2011;18(1):1–30.

    Google Scholar 

  248. Lewis JH. Risk-benefit assessment of new drugs: perspectives of a former FDA Advisory Committee member. Drug Inf J. 1993;27:1037–49.

    Google Scholar 

  249. Nicholson SC, Peterson J, Yektashenas B. Risk evaluation and mitigation strategies (REMS): educating the prescriber. Drug Saf. 2012;35(1):91–104.

    CAS  PubMed  Google Scholar 

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    James H. Lewis

  2. Division of Gastroenterology Hepatology Section, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA

    James H. Lewis

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Lewis, J.H. Drug-Induced Liver Injury Throughout the Drug Development Life Cycle: Where We Have Been, Where We are Now, and Where We are Headed. Perspectives of a Clinical Hepatologist. Pharm Med 27, 165–191 (2013). https://doi.org/10.1007/s40290-013-0015-5

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