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Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo relevance.

McKim JM - Comb. Chem. High Throughput Screen. (2010)

Bottom Line: It is generally recognized that early evaluation of new drug candidates is necessary to improve the process.In vitro cytotoxicity assays have been used for decades as a tool to understand hypotheses driven questions regarding mechanisms of toxicity.This review will focus on the development of an in vitro toxicity screening strategy that is based on a tiered approach to data collection combined with data interpretation.

View Article: PubMed Central - PubMed

Affiliation: CeeTox Inc., 4717 Campus Dr., Kalamazoo, MI 49008, USA. jmckim@ceetox.com

ABSTRACT
One of the greatest challenges facing the pharmaceutical industry today is the failure of promising new drug candidates due to unanticipated adverse effects discovered during preclinical animal safety studies and clinical trials. Late stage attrition increases the time required to bring a new drug to market, inflates development costs, and represents a major source of inefficiency in the drug discovery/development process. It is generally recognized that early evaluation of new drug candidates is necessary to improve the process. Building in vitro data sets that can accurately predict adverse effects in vivo would allow compounds with high risk profiles to be deprioritized, while those that possess the requisite drug attributes and a lower risk profile are brought forward. In vitro cytotoxicity assays have been used for decades as a tool to understand hypotheses driven questions regarding mechanisms of toxicity. However, when used in a prospective manner, they have not been highly predictive of in vivo toxicity. Therefore, the issue may not be how to collect in vitro toxicity data, but rather how to translate in vitro toxicity data into meaningful in vivo effects. This review will focus on the development of an in vitro toxicity screening strategy that is based on a tiered approach to data collection combined with data interpretation.

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A tiered approach to early toxicity screening. A single in vitro screening platform is unlikely to provide the diverse set of data required to evaluate risk and predict in vivo toxicity. Therefore, a tiered systematic approach to in vitro screening should be employed. Solubility, protein binding, an understanding of the relationship between potency and toxicity, and the identification of severe toxicity should be an early consideration. This is followed by detailed information on the mechanism of toxicity and prediction of toxicity in rodents. The identification of compounds that would cause gene toxicity or have a high risk for producing cardiac toxicity should also be determined as early as possible. Potential issues related to drug-drug interactions (DDIs) and species-specific toxicity round out the toxicity profile in late discovery. Prior to selecting a candidate for preclinical development, the compound should be reviewed in terms of therapeutic area, risk/benefit scenarios, and anticipated duration of exposure.
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Figure 3: A tiered approach to early toxicity screening. A single in vitro screening platform is unlikely to provide the diverse set of data required to evaluate risk and predict in vivo toxicity. Therefore, a tiered systematic approach to in vitro screening should be employed. Solubility, protein binding, an understanding of the relationship between potency and toxicity, and the identification of severe toxicity should be an early consideration. This is followed by detailed information on the mechanism of toxicity and prediction of toxicity in rodents. The identification of compounds that would cause gene toxicity or have a high risk for producing cardiac toxicity should also be determined as early as possible. Potential issues related to drug-drug interactions (DDIs) and species-specific toxicity round out the toxicity profile in late discovery. Prior to selecting a candidate for preclinical development, the compound should be reviewed in terms of therapeutic area, risk/benefit scenarios, and anticipated duration of exposure.

Mentions: The challenge is to incorporate methods for evaluating and understanding potential liabilities of NCEs into multiple phases of the drug discovery process. It is unlikely that any one in vitro model would be sufficient as a final decision point for toxicity, but rather a series of models that provide important information at the right time in the discovery pipeline should be used in a tiered approach (Fig. 3). A well defined decision tree should also be part of this screening paradigm. In order to be useful, the in vitro toxicity screening models must be well characterized and predictive of in vivo effects with a low incidence of false positive or negative results. The system should have the capacity to test a large number of molecules in a short period of time with a minimum amount of compound. The data should provide information on potential mechanisms of toxicity, and subcellular targets. Early in the discovery process, when the number of molecules identified as “hits” can be large, in vitro cell-based toxicity assays can be used to rapidly assess potential safety issues associated with a new group of molecules. This information can be used in an iterative manner as chemists modify structures to improve drug-like properties, the modified compound can be retested for toxicity.


Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo relevance.

McKim JM - Comb. Chem. High Throughput Screen. (2010)

A tiered approach to early toxicity screening. A single in vitro screening platform is unlikely to provide the diverse set of data required to evaluate risk and predict in vivo toxicity. Therefore, a tiered systematic approach to in vitro screening should be employed. Solubility, protein binding, an understanding of the relationship between potency and toxicity, and the identification of severe toxicity should be an early consideration. This is followed by detailed information on the mechanism of toxicity and prediction of toxicity in rodents. The identification of compounds that would cause gene toxicity or have a high risk for producing cardiac toxicity should also be determined as early as possible. Potential issues related to drug-drug interactions (DDIs) and species-specific toxicity round out the toxicity profile in late discovery. Prior to selecting a candidate for preclinical development, the compound should be reviewed in terms of therapeutic area, risk/benefit scenarios, and anticipated duration of exposure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908937&req=5

Figure 3: A tiered approach to early toxicity screening. A single in vitro screening platform is unlikely to provide the diverse set of data required to evaluate risk and predict in vivo toxicity. Therefore, a tiered systematic approach to in vitro screening should be employed. Solubility, protein binding, an understanding of the relationship between potency and toxicity, and the identification of severe toxicity should be an early consideration. This is followed by detailed information on the mechanism of toxicity and prediction of toxicity in rodents. The identification of compounds that would cause gene toxicity or have a high risk for producing cardiac toxicity should also be determined as early as possible. Potential issues related to drug-drug interactions (DDIs) and species-specific toxicity round out the toxicity profile in late discovery. Prior to selecting a candidate for preclinical development, the compound should be reviewed in terms of therapeutic area, risk/benefit scenarios, and anticipated duration of exposure.
Mentions: The challenge is to incorporate methods for evaluating and understanding potential liabilities of NCEs into multiple phases of the drug discovery process. It is unlikely that any one in vitro model would be sufficient as a final decision point for toxicity, but rather a series of models that provide important information at the right time in the discovery pipeline should be used in a tiered approach (Fig. 3). A well defined decision tree should also be part of this screening paradigm. In order to be useful, the in vitro toxicity screening models must be well characterized and predictive of in vivo effects with a low incidence of false positive or negative results. The system should have the capacity to test a large number of molecules in a short period of time with a minimum amount of compound. The data should provide information on potential mechanisms of toxicity, and subcellular targets. Early in the discovery process, when the number of molecules identified as “hits” can be large, in vitro cell-based toxicity assays can be used to rapidly assess potential safety issues associated with a new group of molecules. This information can be used in an iterative manner as chemists modify structures to improve drug-like properties, the modified compound can be retested for toxicity.

Bottom Line: It is generally recognized that early evaluation of new drug candidates is necessary to improve the process.In vitro cytotoxicity assays have been used for decades as a tool to understand hypotheses driven questions regarding mechanisms of toxicity.This review will focus on the development of an in vitro toxicity screening strategy that is based on a tiered approach to data collection combined with data interpretation.

View Article: PubMed Central - PubMed

Affiliation: CeeTox Inc., 4717 Campus Dr., Kalamazoo, MI 49008, USA. jmckim@ceetox.com

ABSTRACT
One of the greatest challenges facing the pharmaceutical industry today is the failure of promising new drug candidates due to unanticipated adverse effects discovered during preclinical animal safety studies and clinical trials. Late stage attrition increases the time required to bring a new drug to market, inflates development costs, and represents a major source of inefficiency in the drug discovery/development process. It is generally recognized that early evaluation of new drug candidates is necessary to improve the process. Building in vitro data sets that can accurately predict adverse effects in vivo would allow compounds with high risk profiles to be deprioritized, while those that possess the requisite drug attributes and a lower risk profile are brought forward. In vitro cytotoxicity assays have been used for decades as a tool to understand hypotheses driven questions regarding mechanisms of toxicity. However, when used in a prospective manner, they have not been highly predictive of in vivo toxicity. Therefore, the issue may not be how to collect in vitro toxicity data, but rather how to translate in vitro toxicity data into meaningful in vivo effects. This review will focus on the development of an in vitro toxicity screening strategy that is based on a tiered approach to data collection combined with data interpretation.

Show MeSH
Related in: MedlinePlus