9 A Pair Ranking (PRank) Method for Assessing Assay …
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[26]. TGx methods allow for the screening of drugs, providing accurate results at a
much lower cost than traditional drug development methods. TGx produces results
faster than traditional drug development. However, species differences and the impact
of multiple time/dosage effect still need to be optimized. Here, we summarized the
aims and purpose of an in vitro experiment with different treatment duration to
explain the complexity:
(1) One-day experiment: single dose toxicity studies can be done to establish the
dosage in the clinic and applied to predict diverse toxic response.
(2) Four-day experiment: can demonstrate target-organ toxicity concerns for medicinal chemistry efforts under the specific mechanism of action (MoA).
(3) Seven-day experiment: mainly used to establish the dosage range for non-rodent
animal studies.
(4) Fourteen-day experiment: prerequisite stage to pick the dose for a GLP twentyeight-day repeated dose study.
(5) Twenty-eight-day experiment: a golden standard GLP study to assess the target
organ toxicities and study single ascending dose (SAD) and multiple ascending
doses (MAD) for seeking for first human dose in a clinical trial.
9.2.2 In Vitro Testing Systems
The in vitro assay systems derived from animal or human tissues provide an opportunity to complement long-term animal-based testing procedures, which has been
marked as uncertainty and with limited transferability power [27–29]. High throughput approaches for transcriptional profiling such as in vitro gene expression assays
have been widely applied and intensively explored for its potential capability in both
toxicology and pharmacology fields [30–32]. The evolving nature of genomic technology provides multiple choices on TGx experiment designs for addressing different
toxicological questions. Meanwhile, concerns are also raised on the reproducibility
of genomic technologies due to the complex nature and aspects regarding cell types,
genomics platforms, intro/across laboratory, and data analysis methodologies [33].
9.2.3 Human Toxicity
The objective of either in vitro or in vivo testing systems is to truly reflect the biological response of humans. To select the right testing assay systems for assessing the
toxicity endpoint in human, we need better understanding the etiology and natural
history of human toxicity. Several knowledge bases have been developed to increase
our understanding of toxicity and provide a “one-stop” solution for prediction model
development and new hypothesis generation. For example, NCTR scientists led the
effort to develop a liver toxicity knowledge base (LTKB) to provide different drug
163
[26]. TGx methods allow for the screening of drugs, providing accurate results at a
much lower cost than traditional drug development methods. TGx produces results
faster than traditional drug development. However, species differences and the impact
of multiple time/dosage effect still need to be optimized. Here, we summarized the
aims and purpose of an in vitro experiment with different treatment duration to
explain the complexity:
(1) One-day experiment: single dose toxicity studies can be done to establish the
dosage in the clinic and applied to predict diverse toxic response.
(2) Four-day experiment: can demonstrate target-organ toxicity concerns for medicinal chemistry efforts under the specific mechanism of action (MoA).
(3) Seven-day experiment: mainly used to establish the dosage range for non-rodent
animal studies.
(4) Fourteen-day experiment: prerequisite stage to pick the dose for a GLP twentyeight-day repeated dose study.
(5) Twenty-eight-day experiment: a golden standard GLP study to assess the target
organ toxicities and study single ascending dose (SAD) and multiple ascending
doses (MAD) for seeking for first human dose in a clinical trial.
9.2.2 In Vitro Testing Systems
The in vitro assay systems derived from animal or human tissues provide an opportunity to complement long-term animal-based testing procedures, which has been
marked as uncertainty and with limited transferability power [27–29]. High throughput approaches for transcriptional profiling such as in vitro gene expression assays
have been widely applied and intensively explored for its potential capability in both
toxicology and pharmacology fields [30–32]. The evolving nature of genomic technology provides multiple choices on TGx experiment designs for addressing different
toxicological questions. Meanwhile, concerns are also raised on the reproducibility
of genomic technologies due to the complex nature and aspects regarding cell types,
genomics platforms, intro/across laboratory, and data analysis methodologies [33].
9.2.3 Human Toxicity
The objective of either in vitro or in vivo testing systems is to truly reflect the biological response of humans. To select the right testing assay systems for assessing the
toxicity endpoint in human, we need better understanding the etiology and natural
history of human toxicity. Several knowledge bases have been developed to increase
our understanding of toxicity and provide a “one-stop” solution for prediction model
development and new hypothesis generation. For example, NCTR scientists led the
effort to develop a liver toxicity knowledge base (LTKB) to provide different drug