264
M. Chen et al.
• Similarly, the less-DILI-concern drugs could be reassigned as verified less-DILIconcern (
v Less-DILI-concern) or “Ambiguous DILI-concern,” which will depend
on whether evidence of causality is available.
• The verified no-DILI-concern drug (
v No-DILI-concern) can be confirmed only if
the drug was not verified as a cause of DILI in literature and no DILI mentioned
in its drug label.
The refined schema was applied to 1036 marketed drugs approved by the FDA
before 2010, namely DILIrank dataset, including 192
v Most-DILI-concern drugs,
278
v Less-DILI-concern drugs, 312
v No-DILI-concern drugs, and 254 Ambiguous
DILI drug. Notably, given that the existing knowledge will advance over time, the
schema we applied in the DILIrank will continuously be updated along with the
newly reported DILI cases.
13.3 Predictive Models Developed at NCTR
Developing a risk management plan to improve prediction of a drug’s hepatotoxic
potential is a long-term effort of the research community [41], and predictive models
or biomarkers are essential for assessing the risk for DILI in humans at early stages
of drug development, even before the first test in humans. The developments of
predictive models for DILI are nicely summarized in several seminal reviews [42].
Here, we briefly introduced some continuing efforts at the FDA’s National Center
for Toxicological Research for the developing models to predict the risk for DILI in
humans, such as the “rule-of-two” model, DILI score model, and conventional and
modified Quantitative structure–activity relationship (QSAR) models.
13.3.1 The “Rule-of-Two” Model [11]
Many drugs withdrawn from the market or issued a black box warning due to hepatotoxicity were prescribed at a daily dose of 100 mg or greater [43, 44] while drugs
given at a lower daily dose of <10 mg experienced less severe events, suggesting a
potential relationship between hepatotoxicity risk and daily dose [31, 45]. Consequently, some experts recommended avoiding the development of drugs requiring a
high daily dose to reduce the potential adverse events [42, 46, 47]. Meanwhile, many
drugs given at high daily doses are found with little or no risk of DILI, therefore,
suggesting that daily dose alone is not a reliable approach to guide drug development,
regulatory application, and clinical practice.
Besides daily dose, lipophilicity is an important physicochemical property [48]
and is frequently modulated to improve bioavailability and pharmacological activity.
Lipophilicity could affect hepatocyte uptake and drug ADMET (i.e., absorption,
distribution, metabolism, elimination) behaviors [49], and many lines of evidence
M. Chen et al.
• Similarly, the less-DILI-concern drugs could be reassigned as verified less-DILIconcern (
v Less-DILI-concern) or “Ambiguous DILI-concern,” which will depend
on whether evidence of causality is available.
• The verified no-DILI-concern drug (
v No-DILI-concern) can be confirmed only if
the drug was not verified as a cause of DILI in literature and no DILI mentioned
in its drug label.
The refined schema was applied to 1036 marketed drugs approved by the FDA
before 2010, namely DILIrank dataset, including 192
v Most-DILI-concern drugs,
278
v Less-DILI-concern drugs, 312
v No-DILI-concern drugs, and 254 Ambiguous
DILI drug. Notably, given that the existing knowledge will advance over time, the
schema we applied in the DILIrank will continuously be updated along with the
newly reported DILI cases.
13.3 Predictive Models Developed at NCTR
Developing a risk management plan to improve prediction of a drug’s hepatotoxic
potential is a long-term effort of the research community [41], and predictive models
or biomarkers are essential for assessing the risk for DILI in humans at early stages
of drug development, even before the first test in humans. The developments of
predictive models for DILI are nicely summarized in several seminal reviews [42].
Here, we briefly introduced some continuing efforts at the FDA’s National Center
for Toxicological Research for the developing models to predict the risk for DILI in
humans, such as the “rule-of-two” model, DILI score model, and conventional and
modified Quantitative structure–activity relationship (QSAR) models.
13.3.1 The “Rule-of-Two” Model [11]
Many drugs withdrawn from the market or issued a black box warning due to hepatotoxicity were prescribed at a daily dose of 100 mg or greater [43, 44] while drugs
given at a lower daily dose of <10 mg experienced less severe events, suggesting a
potential relationship between hepatotoxicity risk and daily dose [31, 45]. Consequently, some experts recommended avoiding the development of drugs requiring a
high daily dose to reduce the potential adverse events [42, 46, 47]. Meanwhile, many
drugs given at high daily doses are found with little or no risk of DILI, therefore,
suggesting that daily dose alone is not a reliable approach to guide drug development,
regulatory application, and clinical practice.
Besides daily dose, lipophilicity is an important physicochemical property [48]
and is frequently modulated to improve bioavailability and pharmacological activity.
Lipophilicity could affect hepatocyte uptake and drug ADMET (i.e., absorption,
distribution, metabolism, elimination) behaviors [49], and many lines of evidence