Drug Induced Liver Injury Models

A principal component analysis (PCA) using simple molecular descriptors showed that the training and test sets overlapped. Focusing on compounds with a Tanimoto similarity greater than 0.7 resulted in a test set of 28 compounds, which had Matthews correlation coefficient and concordance statistics that 

---

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

Kia R, Sison RL, Heslop J et al (2013) Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury are we there yet Br J Clin Pharmacol 75(4) 885-896... 

Other Animal Models to Study Drug-Induced Liver Injury.292... 

Relevance of the APAP Model to Other Drugs that Cause Drug-Induced Liver Injury... 

Howell BA, Yang Y, Kumar R, Woodhead JL, Harrill AH, Clewell HJ in, Andersen ME, SUer SQ, Watkins PB. 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. 

Chen M, Bisgin H, Tong L, Hong H, Fang H, Borlak J, Tong W (2014) Toward predictive models for drug-induced liver injury in humans are we there yet Biomark Med 8, 201—13. 

Ekins S, WiUiams AJ, Xu JJ (2010) A predictive ligand-based Bayesian model for human drug-induced liver injury. Drug Metab Dispos 38, 2302—8. 

Howell BA, Siler SQ, Watkins PB (2014a) Use of a systems model of drug-induced liver injury (DlLlsym( )) to elucidate the mechanistic differences between acetaminophen and its less-toxic isomer, AMAP, in mice. Toxicol Lett 226, 163-72. 

Vliegenthart AD, Tucker CS, Del Pozo J, Dear JW (2014) Zebrafish as model organisms for smdying drug-induced liver injury. BrJ Clin Pharmacol 78,1217-27. 

HA, Howell BA (2014) Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury. Front Pharmacol 5, 240. 

TABLE 18.1 Possible Mechanisms of Idioi ncratic Drug-Induced Liver Injury and Models... 

Roth, R.A. and Ganey, P. (2011) Animal models of idiosyncratic drug-induced liver injury—current status. Crit. Rev. Toxicol. 41, 723-739. 

TRANSLATIONAL MECHANISTIC BIOMARKERS AND MODELS FOR PREDICTING DRUG-INDUCED LIVER INJURY CLINICAL TO IN VITRO PERSPECTIVES... 

Due to the aforementioned discrepancy in data availability (especially relevant to translation of toxic effect) and the fact that many clinical endpoints are multi-mechanistic, it is important to stress that each computational step should be well defined and model small steps, for example, a traditional quantitative structure-activity relationship (QSAR) approach based on chemical structure is probably relevant to distinguish hERG binders from nonbinders, but not relevant to model a small set of diverse compounds associated with a complex endpoint such as drug induced liver injury (DILI). A second important factor to consider when construchng in silico safety models is the intended use of the model, and the potential cost associated with false positives versus false negatives from the model. For instance, there is zero... 

APAP is one of the few drugs that provides an experimental animal model of DILI therefore, a large amount of research has focused on the role of the iimate immune system in APAP-induced liver injury. Following APAP overdose, the initial... 

---