Setting clinical exposure levels of concern for drug-induced liver injury (DILI) using mechanistic in vitro assays

Toxicological Sciences

Volumn 147, Issue 2, 2015, Pages 500-514

  Shah, Falgun ^a   Leung, Louis ^a   Barton, Hugh A ^a   Will, Yvonne ^a   Rodrigues, A David ^a   Greene, Nigel ^a,b   Aleo, Michael D ^a  

^a PFIZER INC   (United States)

^b ASTRAZENECA   (United Kingdom)

Author keywords

Drug induced liver injury; Liver Toxicity Knowledge Base; Plasma exposure; Safety margin

Indexed keywords

BILE SALT EXPORT PUMP;

ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG EXPOSURE; HEPG2 CELL LINE; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; LIVER TOXICITY; MAJOR CLINICAL STUDY; MAXIMUM PLASMA CONCENTRATION; MITOCHONDRION; OXIDATIVE PHOSPHORYLATION UNCOUPLING; OXYGEN CONSUMPTION; PLASMA; PREDICTION; RETROSPECTIVE STUDY; SENSITIVITY AND SPECIFICITY; TOXIC HEPATITIS; DRUG-INDUCED LIVER INJURY; MAXIMUM ALLOWABLE CONCENTRATION; STATISTICS AND NUMERICAL DATA; TOXICITY TESTING;

DRUG-INDUCED LIVER INJURY; HUMANS; IN VITRO TECHNIQUES; INHIBITORY CONCENTRATION 50; MAXIMUM ALLOWABLE CONCENTRATION; RETROSPECTIVE STUDIES; TOXICITY TESTS;

EID: 84943812903     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfv152     Document Type: Article

References (48)

1. Aleo, M. D., Luo, Y., Swiss, R., Bonin, P. D., Potter, D. M., and Will, Y. (2014). Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology 60, 1015-1022.
2. Chen, M., Bisgin, H., Tong, L., Hong, H., Fang, H., Borlak, J., and Tong, W. (2014). Toward predictive models for drug-induced liver injury in humans: are we there yet? Biomark. Med. 8, 201-213.
3. Chen, M., Borlak, J., and Tong, W. (2013a). High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 58, 388-396.
4. Chen, M., Hong, H., Fang, H., Kelly, R., Zhou, G., Borlak, J., and Tong, W. (2013b). Quantitative structure-activity relationship models for predicting drug-induced liver injury based on FDA-approved drug labeling annotation and using a large collection of drugs. Toxicol. Sci. 136, 242-249.
5. Chen, M., Vijay, V., Shi, Q., Liu, Z., Fang, H., and Tong, W. (2011). FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov. Today 16, 697-703.
6. Choi, S. (2003). Nefazodone (Serzone) withdrawn because of hepatotoxicity. CMAJ 169, 1187.
7. Dawson, S., Stahl, S., Paul, N., Barber, J., and Kenna, J. G. (2012). In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab. Dispos. 40, 130-138.
8. Feng, B., Xu, J. J., Bi, Y. A., Mireles, R., Davidson, R., Duignan, D. B., Campbell, S., Kostrubsky, V. E., Dunn, M. C., Smith, A. R., et al. (2009). Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP- 724,714. Toxicol. Sci. 108, 492-500.
9. Fromenty, B., and Pessayre, D. (1995). Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101-154.
10. Greene, N., Aleo, M. D., Louise-May, S., Price, D. A., and Will, Y. (2010). Using an in vitro cytotoxicity assay to aid in compound selection for in vivo safety studies. Bioorg. Med. Chem. Lett. 20, 5308-5312.
11. Greene, N., and Song, M. (2011). Predicting in vivo safety characteristics using physiochemical properties and in vitro assays. Future Med. Chem. 3, 1503-1511.
12. Greer, M. L., Smith, T. J., and Kenna, J. G. (2009). Mechanisms of drug hepatotoxicity in man: novel insights provided by the THLE-CYP cell panel. Toxicology 262, 4.
13. Holt, M., and Ju, C. (2010). Drug-induced liver injury. Handb. Exp. Pharmacol. 196, 3-27.
14. Hoofnagle, J. H., Serrano, J., Knoben, J. E., and Navarro, V. J. (2013). LiverTox: a website on drug-induced liver injury. Hepatology 57, 873-874.
15. Howell, B. A., Yang, Y., Kumar, R., Woodhead, J. L., Harrill, A. H., Clewell, H. J., 3rd, Andersen, M. E., Siler, S. Q., and Watkins, P.B. (2012). In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsym: a mechanistic, mathematical model of DILI. J. Pharmacokinet. Pharmacodyn. 39, 527-541.
16. Hynes, J., Marroquin, L. D., Ogurtsov, V. I., Christiansen, K. N., Stevens, G. J., Papkovsky, D. B., and Will, Y. (2006). Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186-200.
17. Hynes, J., Nadanaciva, S., Swiss, R., Carey, C., Kirwan, S., and Will, Y. (2013). A high-throughput dual parameter assay for assessing drug-induced mitochondrial dysfunction provides additional predictivity over two established mitochondrial toxicity assays. Toxicol. in vitro 27, 560-569.
18. Kakuda, T. N. (2000). Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin. Ther. 22, 685-708.
19. Kalliokoski, A., and Niemi, M. (2009). Impact of OATP transporters on pharmacokinetics. Br. J. Pharmacol. 158, 693-705.
20. Kelly, R. P., Garhyan, P., Raddad, E., Fu, H., Lim, C. N., Prince, M. J., Pinaire, J. A., Loh, M. T., and Deeg, M. A. (2015). Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes. Metab. 17, 414-422.
21. Kostrubsky, S. E., Strom, S. C., Kalgutkar, A. S., Kulkarni, S., Atherton, J., Mireles, R., Feng, B., Kubik, R., Hanson, J., Urda, E., et al. (2006). Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. 90, 451-459.
22. Lammert, C., Einarsson, S., Saha, C., Niklasson, A., Bjornsson, E., and Chalasani, N. (2008). Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 47, 2003-2009.
23. Lee, E. W., Lai, Y., Zhang, H., and Unadkat, J. D. (2006). 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. 281, 16700-16706.
24. Leifke, E., Naik, H., Wu, J., Viswanathan, P., Demanno, D., Kipnes, M., and Vakilynejad, M. (2012). A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin. Pharmacol. Ther. 92, 29-39.
25. Maggos, C. (2009). http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a7yX6S3XPHNQ. Accessed January 1, 2015.
26. Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D., and Will, Y. (2007). Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol. Sci. 97, 539-547.
27. Meier, Y., Pauli-Magnus, C., Zanger, U. M., Klein, K., Schaeffeler, E., Nussler, A. K., Nussler, N., Eichelbaum, M., Meier, P. J., and Stieger, B. (2006). Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 44, 62-74.
28. Morgan, R. E., Trauner, M., van Staden, C. J., Lee, P. H., Ramachandran, B., Eschenberg, M., Afshari, C. A., Qualls, C.W., Jr., Lightfoot-Dunn, R., and Hamadeh, H. K. (2010). Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol. Sci. 118, 485-500.
29. Morgan, R. E., van Staden, C. J., Chen, Y., Kalyanaraman, N., Kalanzi, J., Dunn, R. T., 2nd, Afshari, C. A., and Hamadeh, H.K. (2013). A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol. Sci. 136, 216-241.
30. Nakayama, S., Atsumi, R., Takakusa, H., Kobayashi, Y., Kurihara, A., Nagai, Y., Nakai, D., and Okazaki, O. (2009). A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding. Drug Metab. Dispos. 37, 1970-1977.
31. O'Brien, P. J., Irwin, W., Diaz, D., Howard-Cofield, E., Krejsa, C. M., Slaughter, M. R., Gao, B., Kaludercic, N., Angeline, A., Bernardi, P., et al. (2006). High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch. Toxicol. 80, 580-604.
32. Obach, R. S., Lombardo, F., and Waters, N. J. (2008). Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab. Dispos. 36, 1385-1405.
33. Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., Lilly, P., Sanders, J., Sipes, G., Bracken, W., et al. (2000). Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56-67.
34. Porceddu, M., Buron, N., Roussel, C., Labbe, G., Fromenty, B., and Borgne-Sanchez, A. (2012). Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria. Toxicol. Sci. 129, 332-345.
35. Rodrigues, A. D., Lai, Y., Cvijic, M. E., Elkin, L. L., Zvyaga, T., and Soars, M. G. (2014). Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity: mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab. Dispos. 42, 566-574.
36. Roth, R. A., and Ganey, P. E. (2010). Intrinsic versus idiosyncratic drug-induced hepatotoxicity-two villains or one? J. Pharmacol. Exp. Ther. 332, 692-697.
37. Ruddy, M., Pramanik, B., Lunceford, J., Li, S., Cilissen, C., Stoch, A., Wagner, J., Amatruda, J. M., Herman, G., and Kaufman, K. D. (2011). Inhibition of glucagon-induced hyperglycemia predicts glucose lowering efficacy of a glucagon receptor antagonist, MK-0893, in type 2 diabetes (T2DM) [Abstract]. Diabetes 60(Suppl), A85.
38. Shah, F., and Greene, N. (2014). Analysis of Pfizer compounds in EPA's ToxCast chemicals-assay space. Chem. Res. Toxicol. 27, 86-98.
39. Shah, F., Louise-May, S., and Greene, N. (2014). Chemotypes sensitivity and predictivity of in vivo outcomes for cytotoxic assays in THLE and HepG2 cell lines. Bioorg. Med. Chem. Lett. 24, 2753-2757.
40. Shitara, Y., Maeda, K., Ikejiri, K., Yoshida, K., Horie, T., and Sugiyama, Y. (2013). Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm. Drug Dispos. 34, 45-78.
41. Stepan, A. F., Walker, D. P., Bauman, J., Price, D. A., Baillie, T. A., Kalgutkar, A. S., and Aleo, M. D. (2011). 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 United States. Chem. Res. Toxicol. 24, 1345-1410.
42. Thompson, R. A., Isin, E. M., Li, Y., Weidolf, L., Page, K., Wilson, I., Swallow, S., Middleton, B., Stahl, S., Foster, A. J., et al. (2012). In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem. Res. Toxicol. 25, 1616-1632.
43. Usui, T., Mise, M., Hashizume, T., Yabuki, M., and Komuro, S. (2009). Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. Drug Metab. Dispos. 37, 2383-2392.
44. Wager, T. T., Kormos, B. L., Brady, J. T., Will, Y., Aleo, M. D., Stedman, D. B., Kuhn, M., and Chandrasekaran, R. Y. (2013). Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies. J. Med. Chem. 56, 9771-9779.
45. Wang, Y. M., Chai, S. C., Brewer, C. T., and Chen, T. (2014). Pregnane × receptor and drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 10, 1-12.
46. Woodhead, J. L., Yang, K., Siler, S. Q., Watkins, P. B., Brouwer, K. L., Barton, H. A., and Howell, B. A. (2014). Exploring BSEP inhibition- mediated toxicity with a mechanistic model of druginduced liver injury. Front. Pharmacol. 5, 240.
47. Xu, J. J., Henstock, P. V., Dunn, M. C., Smith, A. R., Chabot, J. R., and de Graaf, D. (2008). Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci. 105, 97-105.
48. Yang, K., Woodhead, J. L., Watkins, P. B., Howell, B. A., and Brouwer, K. L. (2014). Systems pharmacology modeling predicts delayed presentation and species differences in bile acid-mediated troglitazone hepatotoxicity. Clin. Pharmacol. Ther. 96, 589-598.