Chapter 3

Drug-Induced Liver Injury (DILI) Classification

and Its Application on Human DILI Risk Prediction
Shraddha Thakkar, Minjun Chen, Huixiao Hong, Zhichao Liu,
Hong Fang, and Weida Tong

Abstract
Drug-induced liver injury (DILI) is one of the primary reasons for drugs being terminated in premarket
studies or being withdrawn from the market after approval. Many new methodologies have been examined
to improve DILI prediction, including high-throughput/high-­ content screening assays, in silico
approaches and toxicogenomics, all of which rely on a truth set of drugs with well-defined DILI potential.
However, defining a drug’s DILI risk is on varying interpretations, leading to differing classification
schemes. Even when the same drug list is employed, variability in scheme affects predictive variables and
models which lead to disparate risk prediction. Each model imbeds truth and knowledge in a different
manner and context. An integrative approach melding models and variables should yield a system with
enhanced prediction accuracy and better characterized mechanisms of action. Toward such an integrative
predictor, we present four different classification schemes, i.e., an FDA labeling data-based approach
(DILIrank dataset), a clinical evidence-based approach (LiverTox dataset), literature-­based approaches
(Greene and Xu datasets), and a registry-based approach (Suzuki dataset). Comparative analyses showed
good general agreement between these approaches, with the most substantial difference observed between
in silico models for drug-centric classification methods (i.e., drug-labeling and literature based approaches)
versus clinical evidence-based methods (i.e., case reports and registry based approaches). The results sug-
gest that substantial benefits can be obtained by consolidating various classification schemes to generate a
larger dataset imbedding more diverse knowledge, and especially the new data streams from emerging
technologies.

Key words Drug-induced liver injury, Risk assessment, DILI classification, Rule-of-two model,
DILIscore model

1  Introduction

Safety contributes significantly to drug attrition [1, 2]. Safety issues

in both preclinical and clinical stages of drug development are a
formidable challenge, especially at the lead optimization and the
early clinical development stages [3]. DILI (Drug-Induced Liver
Injury) is one of the key drug safety issues, which is a frequent
cause of regulatory action such as “Black Box Warning” or denial

Minjun Chen and Yvonne Will (eds.), Drug-Induced Liver Toxicity, Methods in Pharmacology and Toxicology,
https://doi.org/10.1007/978-1-4939-7677-5_3, © Springer Science+Business Media, LLC, part of Springer Nature 2018

45
46 Shraddha Thakkar et al.

in approval [1]. Currently animal models are not effective enough

in prediction of DILI risk in humans, evident by the fact that close
to 50% of drugs failed in the clinical trials due to hepatotoxicity are
not detected by these animal models [4]. Therefore, significant
efforts are needed to bridge the gap and to reduce DILI risk for
humans and improve upon early detection of DILI.
Meanwhile, recent changes in toxicology discipline reveal a
paradigm shift in increasing the efforts to develop alternative meth-
ods with emerging technologies for safety assessment. These
include high throughput in vitro methodologies, in silico
approaches and toxicogenomics, which provide a better under-
standing of mechanism of action and enhances safety related assess-
ments [5]. Several large-scale studies made in this regard are Tox21
[6], ToxCast [7], and EU activities under the REACH initiative
[5] that aim to evaluate the utility of the emerging technologies for
the toxicity assessment. In vitro techniques use both high-­
throughput and high-content screening methodologies to record
the cellular responses of multiple drugs and chemicals. In silico
methods have been developed to predict potential toxicity based
on the chemical structures of compounds. Toxicogenomics exam-
ines the gene activities following chemical exposure to understand
the molecular mechanisms of toxicity. These methodologies usu-
ally involve a training-validation process. Specifically, a predictive
model is constructed first based on a list of compounds (training
set) with known outcomes (e.g., DILI-positive and DILI-negative),
which is followed by a validation step where the model is chal-
lenged using an independent list of compounds (test set) with
known outcomes to assess its validity. As depicted in Fig. 1, a refer-
ence list with a large number of compounds with known outcomes
was used as a foundation to successfully employ these in vitro and
in silico methods. Therefore, a reference drug list with clear and
well-defined DILI classification is important for the development
of predictive models utilizing emerging technologies.
DILI classification is to divide drugs into either binary (e.g.,
DILI-positive or DILI-negative) groups or ordinal classes (most-,
less-, and no-DILI-concern). However, assigning a drug as either
positive or negative for liver injury is a challenge [6]. This is largely
due to the fact that DILI is often associated with a low incidence
(particularly in the study of marketed drugs) but with a wide range
of severity and different injury patterns. In addition, causality of
liver injury (i.e., incriminating the drug for DILI) is frequently
difficult to ascertain due to multiple reasons, e.g., comedication,
alcohol consumption, preexisting liver disease etc. Therefore,
determining the extent of DILI risk for a drug is somewhat subjec-
tive and often based on how we weigh frequency (i.e., how many
incidences deemed significant?), causality (what is the likelihood of
incriminating a drug for DILI?), and severity (how serious the liver
 DILI Classifications and the Predictive Models 47

Fig. 1 Development and performance of a predictive model for assessing the human DILI risk depends heavily
upon the accuracy and consistency of the DILI classification. DILI classification differentiates drugs as DILI
positive (drugs that can cause liver injury) and DILI negative (drugs that have not revealed signs of liver injury),
and used to identify mechanistic parameters using emerging methodologies for DILI prediction. Emerging
technologies used for DILI prediction included, but are not limited to, in vitro methods (e.g., High Content
Screening and High Throughput Screening assays), and in silico methodologies

injury is?) [8]. Using different data sources, (e.g., the number of
case reports [8–12] or FDA approved-drug labeling [8, 13]) and
weighing differently on each of these factors could vary the assign-
ment of DILI classification to the same drugs. In this paper, we
first summarize the four different DILI classifications within five
reported large DILI datasets (n > 200). We then conducted com-
parative analysis between these classification schemas and demon-
strated the variability in classification on the model prediction by
applying our DILIscore model (a quantitative predictive model for
DILI severity).

2  DILI Classifications

Table 1 summarizes five DILI classification datasets for human

hepatotoxicity including >200 drugs. The DILI classification of
all the datasets was for DILI severity assessments (not for injury
patterns or disease types). DILIrank has the largest size, which
overlapped significantly with other four datasets; the number of
48 Shraddha Thakkar et al.

overlapped drugs was shown in the third column of the Table 1

and Fig. 2. Most analyses reported in this paper were applied only
to the overlapped drugs unless specially mentioned.

Table 1
Various DILI classification datasets

DILI No. of drugs DILI classification scheme

classification No. of overlap with DILI evidence (the number of drugs in each
datasetsa drugs DILIrankb information category)c
DILIrank [8] 1036 1036 FDA drug labeling and Four DILI-concern groups:
DILI causality • vNo-DILI-concern (312)
evidence • vLess-DILI-concern (278)
• vMost-DILI-concern (192)
• Ambiguous DILI-­concern
(254)
LiverTox [14] 663 493 (74%) Human DILI case Five DILI likelihood levels:
reports • Category A (36); most likely
• Category B (68)
• Category C (87)
• Category D (108)
• Category E (195); least
likely
Xu et al. [12, 15] 532 343 (64%) Literature evidence and Two categories:
DILI case reports • DILI positive (196)
• DILI negative (147)
Greene et al. [9] 1266 325d (26%) Literature evidence and Three categories
DILI case reports • Human hepatotoxicity (189)
• Weak evidence (50)
• No evidence (86)
Suzuki et al. [16] 385e 287e (75%) Case reports collected Three categories:
by large DILI • General liver injury (157)
registries • Acute liver failure (87)
• Withdrawn or suspension for
DILI (43)
a
The DILI classification datasets were complied from the supplemental tables associated with the original publications,
including DILIrank [8], LiverTox [14], Xu et al. [12, 15], Greene et al. [9] and Suzuki et al. [16]
b
The number of drugs reported from each classification reflect only human data and that were approved from FDA
before 2010
c
The number of drugs reported in each categories of all the classification are only the DILIrank subset
d
Does not contanin the compounds tested on animals
e
Reported list of drug that are hepatotoxic
 DILI Classifications and the Predictive Models 49

Fig. 2 DILIrank data set was generated using FDA drug labeling and DILI causality approach and contains the
drugs approved by the US FDA before 2010. It also contains number of drugs from the other type of DILI clas-
sifications that are overlapped with DILIrank such as Greene (325 drugs), Suzuki (268 drugs), LiverTox (493
drugs), and Xu (343 drugs). This analysis was done to understand the coverage of drugs from each database
and overlapping with others. However, this analysis is independent of DILI classification assigned by each
dataset. Besides DILIrank, other four datasets follow different approaches to identify DILI positive and DILI
negative drugs and there is very little overlap (15.3%) between them. Greene and Xu classifications used simi-
lar approach and thus with the largest overlap (47.5%) while Suzuki’s and LiverTox method contain unique list
of DILI drugs and non-DILI drugs (Those drugs were not identified by any other classification system)

2.1  DILIrank: A Drug The DILIrank dataset contained 1036 drugs approved by the FDA
Labeling Based before 2010 with classified DILI categories [8]. This classification
Approach was based on the FDA drug labeling documents and in addition, it
also accounted for DILI causality evidence in literature. DILI cat-
egories were classified for the drugs as vNo-, vLess-, or vMost-
DILI-Concerns while the drugs that could not be categorized in
the above classification for the DILI concern was classified as
“Ambiguous-DILI-Concern.” vMost-DILI-concern drugs are
50 Shraddha Thakkar et al.

those drugs that were (a) withdrawn due to DILI, or (b) have
“Black-Box Warning and Precautions” labeling section (192
drugs). vLess-DILI-Concern drugs are those drugs that have DILI
statements in “Warning and Precautions” labeling section that rep-
resents only mild indications or DILI indication present in “Adverse
Reactions” section (278 drugs). For drugs recorded with DILI
evidences in drug labeling (i.e., vMost- and vLess-DILI-Concern)
were further verified for their DILI causality in literature, other-
wise they were classified as having “Ambiguous-DILI-Concern” as
such drugs should be used with caution (254 drugs); whereas
v
No-DILI-Concern indicates that there is no DILI indication pres-
ent in any of three labeling sections (i.e., Boxed Warning, Warnings
and Precautions, and Adverse Reactions) and no litrature evidence
available (312 drugs).

2.2  LiverTox: LiverTox database is a collaborative project between two institutes

A Clinical Evidence of National Institute of Health, i.e., National Institute of Diabetes
Based Approach and Digestive and Kidney Diseases (NIDDK) and National Library
of Medicine (NLM) [17]. It contains information about DILI case
reports from prescription and nonprescription drugs and are clas-
sified based on the likelihood of causing liver injury [14]. This
likelihood takes into consideration how often a drug is responsible
in causing liver injury based on the case-reports obtained from lit-
erature. Multiple individual case reports have been used to develop
five point categorization of the DILI likelihood scores [14].
Category A represents the drugs that has >50 case reports demon-
strating liver injury (36 drugs), category B between 12 and 50
cases (68 drugs), category C less than 12 case reports (87 drugs),
and category D three or less case reports per drug (108 drugs).
Category E represents the list of drugs that does not indicate sign
of liver injury even after multiple years of usage (109 drugs). Since
the categories were defined by number of cases, there are more
patients reporting DILI related issues for drugs from category A in
comparison with drugs from category D. Thus drug listed in the
category A will have more chances of DILI likelihood in compari-
son with the other categories.

2.3  Greene This dataset consists of DILI information from both human and
Classification: animal studies, but only human data were used in this paper (shown
A Literature Based in Table 1 column 3 and 5). The number of case reports in con-
Approach junction with literature based evidence were used for human DILI
classification of 325 drugs in Greene classification [9]. Drugs are
classified into human hepatotoxicity (189 drugs) with weak evi-
dence (50 drugs) or no evidence (86 drugs) for DILI.

2.4  Suzuki Classification from Suzuki [16] has consolidated the DILI
Classification: information from major DILI registries, including the Spanish
A Registry Based DILI registry, the Swedish adverse reaction databases and the DILI
Approach ­network from USA. This classification system has identified 157
 DILI Classifications and the Predictive Models 51

drugs with general liver injury and 87 drugs with acute liver failure.
Additionally, 43 drugs were identified as withdrawn or suspended
due to concern for DILI.

2.5  Xu Classification: Xu et al. [15] have classified 343 drugs based on the case reports
A Literature Based and information available in the various literature. The drugs were
Approach classified as either DILI positive or negative. There were 196 drugs
identified as DILI positive and 147 drugs identified as DILI
negative.

3  Comparative Analysis Between Various DILI Classification Schemes

Each classification system mentioned above follows a set of

approaches to identify drugs that have potential to cause liver
injury or not. Specifically, DILIrank classifies the drugs based on
the DILI information that was gathered during preclinical devel-
opment, clinical trials, approval, and postmarket study. The
LiverTox classification is based on the clinical observation and con-
solidates the likelihood to cause the liver injury based on the fre-
quency and severity of clinical observation. Both Greene and Xu
classifications are based on literature evidences and Suzuki is a reg-
istry based approach. Thus, comparative analysis from the various
classification schemes was made to evaluate the variability across
these five datasets.
The analyses were specifically focused on only those drugs
from the four datasets that were present in the DILIrank. As shown
in Fig. 2, the overlap of DILIrank with the other four datasets was
in the following order of Suzuki (75%) > LiverTox (74%) > Xu
(64%) > Greene (26%). The analysis was done to understand the
overlap of the drugs across various databases and it was indepen-
dent of their DILI classification. The result indicates that combin-
ing all these five datasets could generate the largest reference list to
support DILI studies.
As shown in Fig. 3a, concordance between DILIrank and
LiverTox databases was consistent only for those drugs that over-
lap in the following categories (a) vMost-DILI-Concern of
DILIrank and Category A of LiverTox (b) vLess-DILI-Concern of
DILIrank and Category D of LiverTox (c) vNo-DILI-Concern of
DILIrank and Category E of LiverTox. For example, 29 out of 36
drugs (81%) are most likely to cause liver injury (Category A, >50
Cases) as determined by LiverTox were also the vMost-DILI-­
Concern drugs in DILIrank. Similarly, 87 out of 108 drugs (81%)
with lower likelihood to cause liver injury (Category D, 1–3 cases)
by LiverTox were the vLess-DILI-Concern drugs by DILIrank.
Additionally, LiverTox also identified the drugs which have been
used extensively and does not contain any reported DILI case
reports, of which 90 of 100 drugs (90%) were also identified as
v
No-DILI-Concern drugs by DILIrank. The general trend of
52 Shraddha Thakkar et al.

Fig. 3 (a) Comparison of DILIrank with LiverTox database (i.e., the labeling based classification against the
clinical report based classification). (b) Comparison of DILIrank with Greene classification (i.e., the labeling
based classification against a literature based approach). (c) Comparison of DILIrank with Suzuki classification
(i.e., the labeling based classification against the clinical report based classification). (d) Comparison of
DILIrank with Xu classification (i.e., the labeling based classification against the literature based
classification)

overlap by DILI severity is apparent between the two databases.

The comparisons of DILIrank dataset with the Greene dataset
reveal concordance (Fig. 3b). There were overlap in the following
categories (a) vMost-DILI-Concern and vLess-DILI-Concern of
DILIrank compared to Human Hepatotoxicity of Greene (b)
 DILI Classifications and the Predictive Models 53

v
Less-DILI-Concern of DILIrank compared to weak hepatotoxic-
ity of Greene (c) VNo-DILI-Concern of the DILIrank compared
to no hepatotoxicity of Greene. For example, 50 out of 63 drugs
(79%) have no evidence of causing liver injury were also found to
be in the category of no-DILI-Concern drugs in DILIrank.
Similarly, 36 out of 39 drugs (92%) with weak evidence of hepato-
toxicity based on literature evidence are also defined as vLess-DILI-­
Concern by DILIrank. The Human hepatotoxicity classification of
Greene, demonstrated the overlap with vLess-DILI-Concern cate-
gory (39%) as well as vMost-DILI-Concern category (54%). Of
note, Greene classification reports that all the drugs are hepato-
toxic to humans in the human hepatotoxicity category, irrespective
of the severity of the classification. However, majority of drugs
from Human Hepatotoxicity category (86 out of 158 drugs) were
the vMost-DILI-Concern drugs. Thus, Greene classification shows
concordance in data of the general trend in comparison with the
DILIrank dataset.
A similar trend was observed for Xu dataset which is also a
literature-­based approach (Fig. 3d), where 55% of the drugs belong
to the DILI positive categories by Xu are represented in the VMost-­
DILI-­Concern category of DILIrank.
The Suzuki dataset is derived from the DILI information based
on the case registry, which divided the dataset into three categories
based on severity and liver injury risk to humans. Suzuki dataset
contains information related to human hepatotoxicity and it does
not contain the list of drugs that does not cause liver injury. As
depicted in Fig. 3c, all the drugs that are either withdrawn or sus-
pended due to DILI on Suzuki’s are represented in the vMost-
DILI-­Concern category of DILIrank. Additionally, 73% of the
drugs that cause general liver injury in Suzuki dataset belong to the
v
Less-DILI-Concern category of DILIrank.
By comparing DILIrank with other four classification schemes
for the drugs overlapped, there is an apparent trend between these
classification schemes (highlighted as red circles). However, differ-
ences were also observed between data sets, which could affect the
performance of predictive models. Therefore, a predictive model
developed using one classification scheme would not necessary
converge when using a different classification scheme.

4  DILI Classification and Its Influence on Model Development

Various bioinformatics approaches have been employed for the

development of DILI predictive model [18–22] . For example,
to understand the structure and toxicity relationship [21, 23],
we developed a DILI prediction system (called DILIps) [18]. In
addition, we have also developed a “Rule of Two” model (RO2)
to identify drugs that are likely cause of DILI risk in humans [20],
54 Shraddha Thakkar et al.

which specified that an oral medication having high lipophilicity

[24] and high daily dose [25], is statistically significantly associated
with DILI risk in humans [24]. Here, the threshold logP (measured
by its logP ≥ 3) [26] [27] and daily dose of ≥100 mg/day [24]
were determined according to the recommendations from
literature.
By realizing that the reactive metabolites play a major role in
the development of drug toxicity, we incorporated the reactive
metabolite formation into RO2, which yielded a DILIscore model
that allows quantitative assessment of DILI risk [28]. Specifically, a
mathematically derived equation inferred from the analysis of a
dataset including N = 192 FDA approved drugs as given below was
established in DILIscore to quantitatively assess DILI risk based
on the daily dose, lipophilicity, and the formation of reactive
metabolite [29].
DILIscore = 0.608 ´ log ( daily dose / mg ) + 0.227 ´ log P + 2.833 ´ RM.
Here, log (daily dose/mg) is a natural log or equivalent to
ln (daily dose/mg), and the numerical value of 1 or 0 was given
to drugs either producing reactive metabolites or not. In
DILIscore, the score >7 were concomitant with severe clinical
outcome. The DILIscore >3 are associated with the moderate
liver injury. DILIscore of <3 were rarely found to be related to
severe liver injury.
We calculated the scores for each drug shown in Fig. 2 using
DILIscore model, and then generated the density plots of score
from each classification scheme. In an idea situation, for each
classification, the plot should show a complete separation between
different severity groups defined by a classification scheme.
However, the purpose of this analysis was to examine the influ-
ence of various DILI classification systems. If two plots bear simi-
larity, it implies that the two classification schemes corresponding
to these two plots have the similar performance in the context of
the DILI score model.
Evidently, DILIrank, Greene, and Xu datasets had similar
distribution patterns, indicating that these three classification
schemes are consistent. Most sever DILI drugs in these data sets
(i.e., VMost-DILI-Concern drugs in DILIrank, Human
Hepatotoxic drug in Greene and DILI positive drugs in Xu) had
the score of ~7 while DILI negative drugs have lower DILIscore
(i.e., VNo-DILI-­Concern drugs in DILIrank ~2.5, no Hepatotoxic
drug in Greene ~2.5 and DILI negative drugs in Xu ~4) in Fig. 4.
On the contrary, the separation between different severity groups in
both LiverTox and Suzuki classification was less clean, highlighting
the impact of the classification scheme on the performance of
predictive model. Thus, a predictive model using one classification
scheme should be used in the right context and it might not be
applicable to other classification schemes.
 DILI Classifications and the Predictive Models 55

Fig. 4 (a) Comparison of DILIscore hepatotoxicity model with the DILIrank dataset. The DILIrank dataset
classified drugs based on drug labeling. In comparison of DILIrank with the DILIscore, we could demonstrate
some degree of separation in the dataset. The vNo-DILI-Concern drugs (green) and vMost-DILI concern drugs
(pink) showed most amount of separation. Most of the vNo-DILI-Concern drugs (green) had the DILIscore of
~2.5 and most of the vMost-DILI-Concern drugs with the DILIscore of ~7. Weak Hepatotoxic drugs demonstrated
the average DILIscore of ~4. (b) Comparison of DILIscore hepatotoxicity model with the Greene dataset. The
Greene dataset classified drugs based on the literature evidence. On comparison with the DILIscore, we were
able to see some degree of separation in the dataset based on the DILIscore. However, comparing the No
Hepatotoxicity evidence drugs (green) and Human Hepatotoxicity drugs (pink) showed most amount of
­separation. Most of the no DILI evidence drugs had the DILIscore of ~2.5 and most of the Human Hepatotoxicity
drugs with the DILIscore of ~7. Weak Hepatotoxic drugs demonstrated the average DILIscore of ~5.
56 Shraddha Thakkar et al.

Fig. 4 (continued) (c) Comparison of DILIscore hepatotoxicity model with the Xu dataset. The Xu dataset is
derived from the literature based evidence. On comparison with the DILIscore, we were able to see some
degree of separation in the dataset based on the Xu classification. Comparing of DILI Positive (pink) and DILI
negative (green) showed the separation. Majority of drugs with DILI negative annotation at Xu classification
demonstrated DILIscore of ~4. Majority of drugs with DILI Positive annotation from Xu classification demon-
strated DILIscore of ~7. (d) Comparison of DILIscore hepatotoxicity model with the LiverTox data set. The
LiverTox data set classified based on the likelihood of liver injury by considering the patients case reports.
DILIscore gives the quantitative value (−1.9 to 8.64) where higher number denotes, higher hepatotoxicity risk.
On comparison of the LiverTox (category A to E) with the DILIscore distribution was not able to separate drugs
classified based on clinical reports. However, few of the drugs with no hepatotoxic indications (DILIScore) and
no chances (to cause liver injury category E (LiverTox) (green) and fatal hepatotoxic indication with most likely
chances to cause liver injury (pink) were differentiable. Majority of drugs with no likelihood to cause liver injury
from LiverTox demonstrated DILIscore of ~4. Majority of drugs with most likely to cause liver injury from
LiverTox demonstrated DILIscore of ~7. (e) Comparison of DILIscore hepatotoxicity model with the Suzuki
dataset. The Suzuki dataset is derived from the DILI based on case registry based approach. On comparison
with the DILIscore, we were able to see some degree of separation in the dataset based on the Suzuki clas-
sification. A comparison of withdrawn drugs (pink) and general DILI drugs (cream) showed most amount of
separation. Suzuki classification does not classify the list of drugs that did not show

A comparative analysis was conducted to understand the

influence of various DILI classification systems in the DILIscore
prediction (Fig. 4). DILIscore quantitatively models the
hepatotoxicity risk in the LiverTox classification, and the drugs are
classified based on the clinical reports and measures the likelihood
showed good concordance with DILIrank data set. Overall
comparison of the DILIscore distribution from LiverTox and
Greene classification raise an important issue that the observed
variability is brought by the classification data set based on its source
of the information. However, the concordance is demonstrated by
 DILI Classifications and the Predictive Models 57

comparison of the quantitative DILIscore’s average quantitative

values at few categories in both classifications. For example, category
D of LiverTox with the Weak Hepatotoxicity evidence of Greene
and vLess-DILI-­Concern of DILIrank demonstrated the average
DILIscore of ~5. Likewise, Category A of LiverTox with the
Human Hepatotoxicity evidence of Greene and vMost-DILI-
Concern of DILIrank demonstrated the average DILIscore of ~7.
Suzuki and Xu classification also demonstrated the degree of
separation in the on comparison with the DILIscore (Fig. 4a–e).
Even though the model is sufficient enough to differentiate
DILI with VNo-DILI-Concern drugs, variation brought by the
source of the data can modulate the quality of the prediction and
eventually, the reliability and reproducibility for the prediction
model.

5  Conclusion

With the advent of the emerging technologies (e.g., high-­throughput

and high-content screening assays) and in silico methodologies
widely adopted in toxicity studies, it is important to have a reference
list of compounds with accurate DILI classification to develop bio-
markers with these technologies. Such a list could be derived from
different classification schemes. We found that different classification
system using different sources of information can vary in assigning a
drug for DILI and which can also affect the model performance.
A robust predictive model is heavily dependent on dataset size, class
prevalence (e.g., data set size, distribution of Active/Inactive) and
the signal/noise strength for class determination [30]. This study
evaluated and compared five large datasets (>200 drugs) whose
classification was derived from four different approaches. This anal-
ysis offers an opportunity to integrate these methods to combine
these datasets into one consolidated list that covers most of the
drug classes for DILI prediction. This consolidated information has
potential to cover the landscape of DILI information. Using this
comprehensive DILI dataset, the predictive models using the new
data stream from emerging technologies can be robust enough to
identify drug potentially causing DILI at earlier stage and can
reduce the liver injury related attrition.

Disclaimer

The views presented in this chapter do not necessarily reflect current

or future opinion or policy of the US Food and Drug Administration.
Any mention of commercial products is for clarification and not
intended as an endorsement.
58 Shraddha Thakkar et al.
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