Download PDF
Semin Liver Dis 2014; 34(02): 227-239
DOI: 10.1055/s-0034-1375962
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Drug-Induced Liver Injury and Drug Development: Industry Perspective

Arie Regev
1   Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
› Author Affiliations
Further Information

Publication History

Publication Date:
31 May 2014 (online)

    Permissions and Reprints

Abstract

Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

Keywords

Drug-induced liver injury - DILI prediction - Hy's law - causality assessment - drug development
 

  • References

  • 1 Stevens JL, Baker TK. The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov Today 2009; 14 (3-4) 162-167
    CrossrefPubMedGoogle Scholar
  • 2 Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology 2008; 48 (5) 1680-1689
    CrossrefPubMedGoogle Scholar
  • 3 FDA. Guidance for industry. Drug-induced livery injury: premarketing clinical evaluation. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf . Accessed December 17, 2013
    PubMedGoogle Scholar
  • 4 Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006; 354 (7) 731-739
    CrossrefPubMedGoogle Scholar
  • 5 Goodman ZD. Drug hepatotoxicity. Clin Liver Dis 2002; 6 (2) 381-397
    CrossrefPubMedGoogle Scholar
  • 6 Lewis JH, Ahmed M, Shobassy A, Palese C. Drug-induced liver disease. Curr Opin Gastroenterol 2006; 22 (3) 223-233
    CrossrefPubMedGoogle Scholar
  • 7 Bhamidimarri KR, Schiff E. Drug-induced cholestasis. Clin Liver Dis 2013; 17 (4) 519-531 , vii
    CrossrefPubMedGoogle Scholar
  • 8 Patel V, Sanyal AJ. Drug-induced steatohepatitis. Clin Liver Dis 2013; 17 (4) 533-546 , vii
    CrossrefPubMedGoogle Scholar
  • 9 Lewis JH. 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 2013; 27: 165-191
    CrossrefPubMedGoogle Scholar
  • 10 Zimmerman HJ. Drug-induced liver disease. In: Hepatotoxicity, The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999: 428-433
    Google Scholar
  • 11 Zetzel L, Kaplan H. Liver damage concurrent with iproniazid administration. N Engl J Med 1958; 258 (24) 1209-1211
    CrossrefPubMedGoogle Scholar
  • 12 Zimmerman HJ, Rosenblum L, Korn RJ, Feldman PE. Some preliminary clinical and biochemical aspects of liver function in patients receiving iproniazid. Ann N Y Acad Sci 1959; 80: 915-927
    PubMedGoogle Scholar
  • 13 Manier JW, Chang WW, Kirchner JP, Beltaos E. Hepatotoxicity associated with ticrynafen—a uricosuric diuretic. Am J Gastroenterol 1982; 77 (6) 401-404
    PubMedGoogle Scholar
  • 14 Zimmerman HJ, Lewis JH, Ishak KG, Maddrey WC. Ticrynafen-associated hepatic injury: analysis of 340 cases. Hepatology 1984; 4 (2) 315-323
    CrossrefPubMedGoogle Scholar
  • 15 NIDDK. LiverTox, Clinical and research information on drug-induced liver injury. Available at: http://livertox.nlm.nih.gov/Isoniazid.htm . Accessed January 7, 2014
    PubMedGoogle Scholar
  • 16 Walker RM, McElligott TF. Furosemide induced hepatotoxicity. J Pathol 1981; 135 (4) 301-314
    CrossrefPubMedGoogle Scholar
  • 17 Taggart HM, Alderdice JM. Fatal cholestatic jaundice in elderly patients taking benoxaprofen. Br Med J (Clin Res Ed) 1982; 284 (6326) 1372
    CrossrefPubMedGoogle Scholar
  • 18 Hamdy RC, Murnane B, Perera N, Woodcock K, Koch IM. The pharmacokinetics of benoxaprofen in elderly subjects. Eur J Rheumatol Inflamm 1982; 5 (2) 69-75
    PubMedGoogle Scholar
  • 19 Moses PL, Schroeder B, Alkhatib O, Ferrentino N, Suppan T, Lidofsky SD. Severe hepatotoxicity associated with bromfenac sodium. Am J Gastroenterol 1999; 94 (5) 1393-1396
    CrossrefPubMedGoogle Scholar
  • 20 Hunter EB, Johnston PE, Tanner G, Pinson CW, Awad JA. Bromfenac (Duract)-associated hepatic failure requiring liver transplantation. Am J Gastroenterol 1999; 94 (8) 2299-2301
    CrossrefPubMedGoogle Scholar
  • 21 Rabkin JM, Smith MJ, Orloff SL, Corless CL, Stenzel P, Olyaei AJ. Fatal fulminant hepatitis associated with bromfenac use. Ann Pharmacother 1999; 33 (9) 945-947
    CrossrefPubMedGoogle Scholar
  • 22 Fontana RJ, McCashland TM, Benner KG , et al; The Acute Liver Failure Study Group. Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. Liver Transpl Surg 1999; 5 (6) 480-484
    CrossrefPubMedGoogle Scholar
  • 23 Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 1998; 129 (1) 36-38
    CrossrefPubMedGoogle Scholar
  • 24 Vella A, de Groen PC, Dinneen SF. Fatal hepatotoxicity associated with troglitazone. Ann Intern Med 1998; 129 (12) 1080
    PubMedGoogle Scholar
  • 25 Herrine SK, Choudhary C. Severe hepatotoxicity associated with troglitazone. Ann Intern Med 1999; 130 (2) 163-164
    PubMedGoogle Scholar
  • 26 Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998; 338 (13) 916-917
    CrossrefPubMedGoogle Scholar
  • 27 Maria VA, Victorino RM. Hypersensitivity immune reaction as a mechanism for dilevalol-associated hepatitis. Ann Pharmacother 1992; 26 (7-8) 924-926
    PubMedGoogle Scholar
  • 28 He R. 2004, Clinical Review of Exanta (ximelagatran) Tablets, FDA Cardiovascular and Renal Drugs Advisory Committee Briefing Information. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4069B1_01_AstraZeneca-Backgrounder.pdf . Accessed January 7, 2014
    PubMedGoogle Scholar
  • 29 Lee WM, Larrey D, Olsson R , et al. Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf 2005; 28 (4) 351-370
    CrossrefPubMedGoogle Scholar
  • 30 Ainscow EK, Pilling JE, Brown NM , et al. Investigations into the liver effects of ximelagatran using high content screening of primary human hepatocyte cultures. Expert Opin Drug Saf 2008; 7 (4) 351-365
    CrossrefPubMedGoogle Scholar
  • 31 Kenne K, Skanberg I, Glinghammar B , et al. Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol In Vitro 2008; 22 (3) 730-746
    CrossrefPubMedGoogle Scholar
  • 32 Kramer JA, Sagartz JE, Morris DL. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat Rev Drug Discov 2007; 6 (8) 636-649
    CrossrefPubMedGoogle Scholar
  • 33 Olson H, Betton G, Robinson D , et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000; 32 (1) 56-67
    CrossrefPubMedGoogle Scholar
  • 34 Release of Guidance Document Pre-market evaluation of hepatotoxicity in health Products. Available at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/hepatotox_guide_ld-eng.pdf Accessed January 10, 2014
    PubMed
  • 35 Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol 2008; 21 (1) 84-92
    CrossrefPubMedGoogle Scholar
  • 36 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) 336-339
    CrossrefPubMedGoogle Scholar
  • 37 Kornbrust DJ, MacDonald JS, Peter CP , et al. Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits. J Pharmacol Exp Ther 1989; 248 (2) 498-505
    PubMedGoogle Scholar
  • 38 Roth RA, Ganey PE. Animal models of idiosyncratic drug-induced liver injury—current status. Crit Rev Toxicol 2011; 41 (9) 723-739
    CrossrefPubMedGoogle Scholar
  • 39 Corsini A, Ganey P, Ju C , et al. Current challenges and controversies in drug-induced liver injury. Drug Saf 2012; 35 (12) 1099-1117
    PubMedGoogle Scholar
  • 40 Katoh M, Matsui T, Nakajima M , et al. Expression of human cytochromes P450 in chimeric mice with humanized liver. Drug Metab Dispos 2004; 32 (12) 1402-1410
    CrossrefPubMedGoogle Scholar
  • 41 Antoine DJ, Williams DP, Park BK. Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science. Expert Opin Drug Metab Toxicol 2008; 4 (11) 1415-1427
    CrossrefPubMedGoogle Scholar
  • 42 Kalgutkar AS, Gardner I, Obach RS , et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 2005; 6 (3) 161-225
    CrossrefPubMedGoogle Scholar
  • 43 Williams DP. Toxicophores: investigations in drug safety. Toxicology 2006; 226 (1) 1-11
    CrossrefPubMedGoogle Scholar
  • 44 Iwanaga T, Nakakariya M, Yabuuchi H, Maeda T, Tamai I. Involvement of bile salt export pump in flutamide-induced cholestatic hepatitis. Biol Pharm Bull 2007; 30 (4) 739-744
    CrossrefPubMedGoogle Scholar
  • 45 Usui T, Mise M, Hashizume T, Yabuki M, Komuro S. Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. Drug Metab Dispos 2009; 37 (12) 2383-2392
    CrossrefPubMedGoogle Scholar
  • 46 Obach RS, Kalgutkar AS, Soglia JR, Zhao SX. Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 2008; 21 (9) 1814-1822
    CrossrefPubMedGoogle Scholar
  • 47 Park BK, Boobis A, Clarke S , et al. Managing the challenge of chemically reactive metabolites in drug development. Nat Rev Drug Discov 2011; 10 (4) 292-306
    CrossrefPubMedGoogle Scholar
  • 48 Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 1994; 271 (13) 992-998
    CrossrefPubMedGoogle Scholar
  • 49 Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004; 127 (6) 1760-1774
    CrossrefPubMedGoogle Scholar
  • 50 Liu ZX, Han D, Gunawan B, Kaplowitz N. Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 2006; 43 (6) 1220-1230
    CrossrefPubMedGoogle Scholar
  • 51 Persson M, Løye AF, Mow T, Hornberg JJ. A high content screening assay to predict human drug-induced liver injury during drug discovery. J Pharmacol Toxicol Methods 2013; 68 (3) 302-313
    CrossrefPubMedGoogle Scholar
  • 52 Przybylak KR, Cronin MT. In silico models for drug-induced liver injury—current status. Expert Opin Drug Metab Toxicol 2012; 8 (2) 201-217
    CrossrefPubMedGoogle Scholar
  • 53 Zhang M, Chen M, Tong W. Is toxicogenomics a more reliable and sensitive biomarker than conventional indicators from rats to predict drug-induced liver injury in humans?. Chem Res Toxicol 2012; 25 (1) 122-129
    CrossrefPubMedGoogle Scholar
  • 54 Low Y, Uehara T, Minowa Y , et al. Predicting drug-induced hepatotoxicity using QSAR and toxicogenomics approaches. Chem Res Toxicol 2011; 24 (8) 1251-1262
    CrossrefPubMedGoogle Scholar
  • 55 Corvi R, Ahr HJ, Albertini S , et al. Meeting report: Validation of toxicogenomics-based test systems: ECVAM-ICCVAM/NICEATM considerations for regulatory use. Environ Health Perspect 2006; 114 (3) 420-429
    CrossrefPubMedGoogle Scholar
  • 56 Senior John . Lessons from isoniazid. Would it be approved today? Available at: www.fda.gov/downloads/Drugs/ScienceResearch/.../ucm076755.pdf . Accessed January 7, 2014
    PubMed
  • 57 Mitchell JR, Long MW, Thorgeirsson UP, Jollow DJ. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy. Chest 1975; 68 (2) 181-190
    CrossrefPubMedGoogle Scholar
  • 58 Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281 (11) 1014-1018
    CrossrefPubMedGoogle Scholar
  • 59 Harrill AH, Roach J, Fier I , et al. The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin Pharmacol Ther 2012; 92 (2) 214-220
    CrossrefPubMedGoogle Scholar
  • 60 Cohen DE, Anania FA, Chalasani N ; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97 (8A) 77C-81C
    PubMedGoogle Scholar
  • 61 Olsson R, Korsan-Bengtsen BM, Korsan-Bengtsen K, Lennartsson J, Waldenström J. Serum aminotransferases after low-dose heparin treatment. Short communication. Acta Med Scand 1978; 204 (3) 229-230
    PubMedGoogle Scholar
  • 62 Dukes Jr GE, Sanders SW, Russo Jr J , et al. Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 1984; 100 (5) 646-650
    CrossrefPubMedGoogle Scholar
  • 63 Carlson MK, Gleason PP, Sen S. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparin-induced hepatotoxicity. Pharmacotherapy 2001; 21 (1) 108-113
    CrossrefPubMedGoogle Scholar
  • 64 Lucena MI, Molokhia M, Shen Y , et al; Spanish DILI Registry; EUDRAGENE; DILIN; DILIGEN; International SAEC. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 2011; 141 (1) 338-347
    CrossrefPubMedGoogle Scholar
  • 65 Kleiner DE, Gaffey MJ, Sallie R , et al. Histopathologic changes associated with fialuridine hepatotoxicity. Mod Pathol 1997; 10 (3) 192-199
    PubMedGoogle Scholar
  • 66 Berends MAM, Snoek J, de Jong EM , et al. Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent. Aliment Pharmacol Ther 2006; 24 (5) 805-811
    CrossrefPubMedGoogle Scholar
  • 67 Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006; 15 (4) 241-243
    CrossrefPubMedGoogle Scholar
  • 68 Senior JR. Regulatory perspectives. In: Kaplowitz N, DeLeve LD, , eds. Drug-Induced Liver Disease. New York, NY: Marcel Dekker; 2003: 739-754
    Google Scholar
  • 69 Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005; 42 (2) 481-489
    CrossrefPubMedGoogle Scholar
  • 70 Andrade RJ, Lucena MI, Fernández MC , et al; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129 (2) 512-521
    CrossrefPubMedGoogle Scholar
  • 71 Food and Drug Administration. Guidance for clinical trial sponsors on the establishment and operation of clinical trial data monitoring committees. Available at: http://www.fda.gov/downloads/Regulatoryinformation/Guidances/ucm127073.pdf . Accessed January 7, 2014
    PubMedGoogle Scholar
  • 72 Slutsky AS, Lavery JV. Data safety and monitoring boards. N Engl J Med 2004; 350 (11) 1143-1147
    CrossrefPubMedGoogle Scholar
  • 73 Guo T, Gelperin K, Senior J. A tool to help you decide (detect potentially serious liver injury). . Available at: http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm076777.pdf . Accessed December 17, 2009
    PubMedGoogle Scholar
  • 74 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) 243-252
    CrossrefPubMedGoogle Scholar
  • 75 Chitturi S, Farrell GC. Drug induced liver disease. In: Schiff ER, et al, eds. Schiff's diseases of the liver. 11th ed. Hoboken, NJ: Wiley-Blackwell; 2012: 703-782
    Google Scholar
  • 76 Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007; 11 (3) 477-505 , v
    CrossrefPubMedGoogle Scholar
  • 77 Fontana RJ, Watkins PB, Bonkovsky HL , et al; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf 2009; 32 (1) 55-68
    CrossrefPubMedGoogle Scholar
  • 78 Starkey Lewis PJ, Dear J, Platt V , et al. Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 2011; 54 (5) 1767-1776
    CrossrefPubMedGoogle Scholar
  • 79 Locke JE, Sun Z, Warren DS , et al. Generation of humanized animal livers using embryoid body-derived stem cell transplant. Ann Surg 2008; 248 (3) 487-493
    PubMedGoogle Scholar