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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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Related in: MedlinePlus

Effects of protein binding on `in vitro` toxicity. The toxicity of drugs with a high affinity for proteins (low Kd) is affected by the amount of protein in the in vitro test system. The response profiles depicted in the graphs demonstrate how the toxicity of a drug can be changed by the amount of protein in the test system. Compounds evaluated early in discovery that show low in vitro toxicity in the presence of high protein concentrations (>10%) should be tested for protein binding. In the example shown, the test compound was evaluated in the presence of 20, 10, and 5% serum. Values represent the mean of 4-5 wells. The coefficient of variation was between 10% and 15% across the assays. Standard error of the mean bars are not shown for clarity.
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Figure 13: Effects of protein binding on `in vitro` toxicity. The toxicity of drugs with a high affinity for proteins (low Kd) is affected by the amount of protein in the in vitro test system. The response profiles depicted in the graphs demonstrate how the toxicity of a drug can be changed by the amount of protein in the test system. Compounds evaluated early in discovery that show low in vitro toxicity in the presence of high protein concentrations (>10%) should be tested for protein binding. In the example shown, the test compound was evaluated in the presence of 20, 10, and 5% serum. Values represent the mean of 4-5 wells. The coefficient of variation was between 10% and 15% across the assays. Standard error of the mean bars are not shown for clarity.

Mentions: New drug candidates with high affinity protein binding are less desirable. In vitro screening data that are negative for toxicity should be a flag for potential protein binding. The effect of protein binding on cytotoxicity can be addressed by conducting a serum titration experiment. The test drug is exposed to the cell system in the presence of decreasing amounts of serum protein (Fig. 13). A shift in the response curve to the left indicates high affinity (low Kd) binding. The data for the test compound shown in Fig. (13) indicate how the toxicity of a drug that has high binding affinity for plasma proteins is controlled by the amount of protein present in the in vitro system.


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)

Effects of protein binding on `in vitro` toxicity. The toxicity of drugs with a high affinity for proteins (low Kd) is affected by the amount of protein in the in vitro test system. The response profiles depicted in the graphs demonstrate how the toxicity of a drug can be changed by the amount of protein in the test system. Compounds evaluated early in discovery that show low in vitro toxicity in the presence of high protein concentrations (>10%) should be tested for protein binding. In the example shown, the test compound was evaluated in the presence of 20, 10, and 5% serum. Values represent the mean of 4-5 wells. The coefficient of variation was between 10% and 15% across the assays. Standard error of the mean bars are not shown for clarity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 13: Effects of protein binding on `in vitro` toxicity. The toxicity of drugs with a high affinity for proteins (low Kd) is affected by the amount of protein in the in vitro test system. The response profiles depicted in the graphs demonstrate how the toxicity of a drug can be changed by the amount of protein in the test system. Compounds evaluated early in discovery that show low in vitro toxicity in the presence of high protein concentrations (>10%) should be tested for protein binding. In the example shown, the test compound was evaluated in the presence of 20, 10, and 5% serum. Values represent the mean of 4-5 wells. The coefficient of variation was between 10% and 15% across the assays. Standard error of the mean bars are not shown for clarity.
Mentions: New drug candidates with high affinity protein binding are less desirable. In vitro screening data that are negative for toxicity should be a flag for potential protein binding. The effect of protein binding on cytotoxicity can be addressed by conducting a serum titration experiment. The test drug is exposed to the cell system in the presence of decreasing amounts of serum protein (Fig. 13). A shift in the response curve to the left indicates high affinity (low Kd) binding. The data for the test compound shown in Fig. (13) indicate how the toxicity of a drug that has high binding affinity for plasma proteins is controlled by the amount of protein present in the in vitro system.

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