Abstract
Drug-induced liver injury (DILI) is the most common organ toxicity encountered in regulatory animal toxicology studies required prior to the clinical development of new drug candidates. Very few reports have evaluated the value of these studies for predicting DILI in humans. Indeed, compounds inducing liver toxicity in regulatory toxicology studies are not always correlated with a risk of DILI in humans. Conversely, compounds associated with the occurrence of DILI in phase 3 studies or after market release are often tested negative in regulatory toxicology studies. Idiosyncratic DILI is a rare event that is precipitated in an individual by the simultaneous occurrence of several critical factors. These factors may relate to the host (e.g. human leukocyte antigen polymorphism, inflammation), the drug (e.g. reactive metabolites) or the environment (e.g. diet/microbiota). This type of toxicity therefore cannot be detected in conventional animal toxicology studies. Several animal models have recently been proposed for the identification of drugs with the potential to cause idiosyncratic DILI: rats treated with lipopolysaccharide, Sod2+/- mice, panels of inbred mouse strains or chimeric mice with humanized livers. These models are not suitable for use in the prospective screening of new drug candidates. Humans therefore constitute the best model for predicting and assessing idiopathic DILI.
References
1.
Ballet F: Hepatotoxicity in drug development: detection, significance and solutions. J Hepatol 1997;26(suppl 2):26-36.
2.
Greaves P, Williams A, Eve M: First doses of potential new medicines to humans: how animals help. Nat Rev Drug Discov 2004;3:226-236.
3.
Baldrick P: Safety evaluation to support first-in-man investigations. II. Toxicology studies. Regul Toxicol Pharmacol 2008;51:237-243.
4.
Horner S, Ryan D, Robinson S, Callander R, Stamp K, Roberts RA: Target organ toxicities in studies conducted to support first time in man dosing: an analysis across species and therapy areas. Regul Toxicol Pharmacol 2013;65:334-343.
5.
Bénichou C: Criteria of drug-induced liver disorders: report of an international consensus meeting. J Hepatol 1990;11:272-276.
6.
Danan G, Bénichou 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;46:1323-1330.
7.
Kornbrust DJ, MacDonald JS, Peter CP, Duchai DM, Stubbs RJ, Germershausen JI, Alberts AW: Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits. J Pharmacol Exp Ther 1989;248:498-505.
8.
Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, Chalasani N, Bonkovsky HL: Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 2014;60:679-686.
9.
Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, van Deun K, Smith P, Berger B, Heller A: Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000;32:56-67.
10.
McKenzie R , Fried MW , Sallie R , Conjeevaram H , Di Bisceglie AM , Park Y, Savarese B, Kleiner D, Tsokos M, Luciano C, Pruett T, Stotka J, Straus SE, Hoofnagle JH: Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med 1995;333:1099-1105.
11.
Lee EW, Lai Y, Zhang H, Unadkat JD: Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine. J Biol Chem 2006;281:16700-16706.
12.
Uetrecht J: Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 2007;47:513-539.
13.
Lee WM, Larrey D, Olsson R, et al: Hepatic findings in long-term clinical trial of ximelagatran. Drug Safety 2005;28:351-370.
14.
Chojkier M: Troglitazone and liver injury: in search of answers. Hepatology 2005;41:237-247.
15.
Bannwarth B, Berenbaum F: Lumiracoxib in the management of osteoarthritis and acute pain. Expert Opin Pharmacother 2007;8:1551-1564.
16.
Boelsterli UA: Idiosyncratic drug hepatotoxicity revisited: new insights from mechanistic toxicology. Toxicol Mech Methods 2003;13:3-20.
17.
Li AP: A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘multiple determinant hypothesis' for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 2002;142:7-23.
18.
Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N: Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 2008;47:2003-2009.
19.
Nolan JP: The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology 2010;52:1829-1835.
20.
Thurman RG, Bradford BU, Limuro Y, Knecht KT, Arteel GE, Yin M, Connor HD, Wall C, Raleigh JA, Frankenberg MV, Adachi Y, Forman DT, Brenner D, Kadiiska M, Mason RP: The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury. J Gastroenterol Hepatol 1998;13(suppl):S39-S50.
21.
Waring JF, Liguori ML, Luyendyk JP, Maddox JF, Ganey, Stachlewitz RF, North C, Blomme EAG, Roth RA: Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 2006;316:1080-1087.
22.
Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA: Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 2007;100:259-266.
23.
Deng X, Luyendik JP, Ganey PE, Roth RA: Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol Rev 2009;61:262-282.
24.
Pessayre D, Fromenty B, Berson A, Robin MA, Letteron P, Moreau R, Mansouri A: Central role of mitochondria in drug-induced liver injury. Drug Metab Rev 2012;44:34-87.
25.
Boelsterli UA, Lim PLK: Mitochondrial abnormalities: a link to idiosyncratic hepatotoxicity? Toxicol Appl Pharmacol 2006;220:92-107.
26.
Ong MMK, Latchoumycandane C, Boelsterli UA: Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci 2007;97:205-213.
27.
Fujimoto K, Kumagai K, Ito K, Arakawa S, Ando Y, Oda S, Yamoto T, Manabe S: Sensitivity of liver injury in heterozygous Sod2 knockout mice treated with troglitazone or acetaminophen. Toxicol Pathol 2009;37:193-200.
28.
Jaeschke H, McGill MR, Ramachandran A: Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 2012;44:88-106.
29.
Beck JA, Lloyd S, Hafezparast M, Lennon-Pierce M, Eppig JT, Festing MF, Fisher EM: Genealogies of mouse inbred strains. Nat Genet 2000;24:23-25.
30.
Bogue MA, Grubb SC: The mouse phenome project. Genetica 2004;122:71-74.
31.
Harrill AH, Watkins PB, Su S, Ross PK, Harbourt DE, Stylianou IM, Boorman GA, Russo MW, Sackler RS, Harris SC, Smith PC, Tennant R, Bogue M, Paigen K, Harris C, Contractor T, Wiltshire T, Rusyn I, Threadgill DW: Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res 2009;19:1507-1515.
32.
Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC: Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296:87-93.
33.
Foster JR, Lund G, Sapelnikova S, Tyrrell DL, Kneteman NM: Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies. Xenobiotica 2014;44:109-122.
34.
Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnai M, et al: The reconstituted ‘humanized liver' in TK-NOG mice is mature and functional. Biochem Biophys Res Commun 2011;405:405-410.
35.
Xu D, Nishimura T, Nishimura S, Zhang H, Zheng M, et al: Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing. PLoS Med 2014;11:e1001628.
36.
Kakuni M, Morita M, Matsuo K, Katoh Y, Nakajima M, Tateno C, Yokoi T: Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury. Toxicol Lett 2012;214:9-18.
37.
Ju C, Reilly T: Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev 2012;44:107-115.
38.
Daly AK, Day CP: Genetic association studies in drug-induced liver injury. Drug Metab Rev 2012;44:116-126.
39.
You Q, Cheng L, Reilly TP, Wegmann D, Ju C: Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 2006;44:1421-1431.
40.
Metushi IG, Uetrecht J: Isoniazid-induced liver injury and immune response in mice. J Immunotoxicol 2014;11:383-392.
41.
Metushi IG, Cai P, Dervovic D, Liu F, Lobach A, Nakagawa T, Uetrecht J: Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset. J Immunotoxicol 2014, Epub ahead of print.
42.
Blomme EA, Yang Y, Waring JF: Use of toxicogenomics to understand mechanisms of drug-induced hepatotoxicity during drug discovery and development. Toxicol Lett 2009;186:22-31.
43.
Chen M, Zhang M, Borlak J, Tong W: A decade of toxicogenomic research and its contribution to toxicological science. Toxicol Sci 2012;130:217-228.
44.
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;25:122-129.
45.
Laifenfeld D, Qiu L, Swiss R, Park J, Macoritto M, Will Y, Younis HS, Lawton M: Utilization of causal reasoning of hepatic gene expression in rats to identify molecular pathways of idiosyncratic drug-induced liver injury. Toxicol Sci 2014;137:234-248.
46.
Mattes W, Davis K, Fabian E, Greenhawc J, Herold M, Looser R, Mellert W, Groeters S, Marxfeld H, Moeller N, Montoya-Parra G, Prokoudine A, van Ravenzwaay B, Strauss V, Walk T, Kamp H: Detection of hepatotoxicity potential with metabolite (metabolomics) profiling of rat plasma. Toxicol Lett 2014;230:467-478.
47.
Bell LN, Vuppalanchi R, Watkins PB, Bonkovsky HL, Serrano J, Fontana RJ, Wang M, Rochon J, Chalasani N, US Drug-Induced Liver Injury Network (DILIN) Research Group: Serum proteomic profiling in patients with drug-induced liver injury. Aliment Pharmacol Ther 2012;35:600-612.
48.
Andersson U, Lindberg J, Wang S, Balasubramanian R, Marcusson-Ståhl M, Hannula M, Zeng C, Juhasz PJ, Kolmert J, Bäckström J, Nord L, Nilsson K, Martin S, Glinghammar B, Cederbrant K, Schuppe-Koistinen I: A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran. Biomarkers 2009;14:572-586.
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