13 Predicting the Risks of Drug-Induced Liver Injury …
265
also implicate lipophilicity to be linked to drug toxicity. Nonetheless, it was unclear
whether the combination of daily dose and lipophilicity related to risk for DILI in
humans.
To better examine the combined effects of daily dose and lipophilicity, a data
repository of 164 drugs labeled for their liver liabilities derived from the LTKBbenchmark dataset were used, including N = 116 most-DILI-concern drugs and N =
48 no-DILI-concern drugs. Lipophilicity was measured by the octanol-water partition
coefficient (i.e., logP) which was calculated from the atomic-based prediction of
AlogP using Pipeline Pilot (version 8.0, Accelrys Inc, San Diego, CA), and it was
categorized into three groups: <1, 1–3, and ≥3 as recommended by literature (13).
Daily doses were majorly retrieved from the WHO’s ATC database (http://www.
whocc.no/atc_ddd_index) and were divided into the groups of <100 mg, 10–100 mg,
and ≥100 mg per day as suggested by literature [43, 46].
When the 164 drugs of the dataset were put into the scatter plot of daily doses
and logP, the upper right quadrant at a high daily dose and a high logP was majorly
distributed with most-DILI-concern drugs. Few no-DILI-concern drugs appeared in
this region. The relative risk for DILI associated with various doses and logP constellations was further assessed. Specifically, the subgroup of daily doses ≥100 mg and
logP ≥ 3 was associated with a significantly higher proportion of hepatotoxic drugs
as compared to the rest of subgroups altogether (96% vs. 41%, odds ratio: 14.05, P <
0.001). The analysis demonstrated that a statistically significant association between
logP and risk for DILI was observed for the drugs given at daily doses of ≥ 100 mg,
while no statistically significant relationship between logP and hepatotoxicity was
obtained for the drugs given at daily doses of less than 100 mg.
Similar findings were observed from another independent dataset of 179 oral
drugs that 85% of the “rule-of-two” positives are associated with hepatotoxicity as
compared with 59% in the “rule-of-two” negatives (odds ratio: 3.89, P < 0.01). These
evidences together suggest that a drug given at a daily dose of ≥100 mg and with a
high logP ≥ 3, namely as the “rule-of-two,” is associated with a significant high risk
for DILI in humans.
The “rule-of-two” is a simple but effective model to predict the risk for DILI
in humans and has been independently evaluated by the drug safety scientists. In a
study by Paul Leeson from UK [50], the “rule-of-two” was applied to predict the
drugs that failed in drug development due to hepatotoxicity in humans, and 13 of 22
(59%) failed drug candidates were found as “rule-of-two” positives (see Table 13.1).
This practice demonstrated that the “rule-of-two” model can be applied to assess
drug candidates with similar or even better performance than that among marketed
drugs, even though the chemical spaces of drugs candidates in development has
significantly shifted from those marketed drugs approved decades ago. Furthermore,
another study from a Pfizer team found that the “rule-of-two” model performs better
than the three mechanistic endpoints they selected (i.e., cytotoxicity, mitochondrial
impairment, and BSEP inhibition) by single, dual combination or triple combinations
when evaluated by a total of 125 drugs [51]. Moreover, the “rule-of-two” model was
also applied to the direct-acting antiviral for the treatment of chronic hepatitis C and
successfully identified the DILI potential associated with Vieraki Pak [52].
265
also implicate lipophilicity to be linked to drug toxicity. Nonetheless, it was unclear
whether the combination of daily dose and lipophilicity related to risk for DILI in
humans.
To better examine the combined effects of daily dose and lipophilicity, a data
repository of 164 drugs labeled for their liver liabilities derived from the LTKBbenchmark dataset were used, including N = 116 most-DILI-concern drugs and N =
48 no-DILI-concern drugs. Lipophilicity was measured by the octanol-water partition
coefficient (i.e., logP) which was calculated from the atomic-based prediction of
AlogP using Pipeline Pilot (version 8.0, Accelrys Inc, San Diego, CA), and it was
categorized into three groups: <1, 1–3, and ≥3 as recommended by literature (13).
Daily doses were majorly retrieved from the WHO’s ATC database (http://www.
whocc.no/atc_ddd_index) and were divided into the groups of <100 mg, 10–100 mg,
and ≥100 mg per day as suggested by literature [43, 46].
When the 164 drugs of the dataset were put into the scatter plot of daily doses
and logP, the upper right quadrant at a high daily dose and a high logP was majorly
distributed with most-DILI-concern drugs. Few no-DILI-concern drugs appeared in
this region. The relative risk for DILI associated with various doses and logP constellations was further assessed. Specifically, the subgroup of daily doses ≥100 mg and
logP ≥ 3 was associated with a significantly higher proportion of hepatotoxic drugs
as compared to the rest of subgroups altogether (96% vs. 41%, odds ratio: 14.05, P <
0.001). The analysis demonstrated that a statistically significant association between
logP and risk for DILI was observed for the drugs given at daily doses of ≥ 100 mg,
while no statistically significant relationship between logP and hepatotoxicity was
obtained for the drugs given at daily doses of less than 100 mg.
Similar findings were observed from another independent dataset of 179 oral
drugs that 85% of the “rule-of-two” positives are associated with hepatotoxicity as
compared with 59% in the “rule-of-two” negatives (odds ratio: 3.89, P < 0.01). These
evidences together suggest that a drug given at a daily dose of ≥100 mg and with a
high logP ≥ 3, namely as the “rule-of-two,” is associated with a significant high risk
for DILI in humans.
The “rule-of-two” is a simple but effective model to predict the risk for DILI
in humans and has been independently evaluated by the drug safety scientists. In a
study by Paul Leeson from UK [50], the “rule-of-two” was applied to predict the
drugs that failed in drug development due to hepatotoxicity in humans, and 13 of 22
(59%) failed drug candidates were found as “rule-of-two” positives (see Table 13.1).
This practice demonstrated that the “rule-of-two” model can be applied to assess
drug candidates with similar or even better performance than that among marketed
drugs, even though the chemical spaces of drugs candidates in development has
significantly shifted from those marketed drugs approved decades ago. Furthermore,
another study from a Pfizer team found that the “rule-of-two” model performs better
than the three mechanistic endpoints they selected (i.e., cytotoxicity, mitochondrial
impairment, and BSEP inhibition) by single, dual combination or triple combinations
when evaluated by a total of 125 drugs [51]. Moreover, the “rule-of-two” model was
also applied to the direct-acting antiviral for the treatment of chronic hepatitis C and
successfully identified the DILI potential associated with Vieraki Pak [52].