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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

Diagrammatic representation of the major steps in the drug discovery process. A typical path for drug discovery is presented. Compounds in a chemical library are screened to identify those molecules that interact with the intended target. Molecules that are positive in this assay “Hits” begin the process of lead identification (Hit-to-Lead) and Lead optimization. In Vitro toxicity screening as well as screens designed to identify ADME, genotoxicity, and cardiac toxicity should be done early in this process in order to identify high risk molecules early.
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Figure 1: Diagrammatic representation of the major steps in the drug discovery process. A typical path for drug discovery is presented. Compounds in a chemical library are screened to identify those molecules that interact with the intended target. Molecules that are positive in this assay “Hits” begin the process of lead identification (Hit-to-Lead) and Lead optimization. In Vitro toxicity screening as well as screens designed to identify ADME, genotoxicity, and cardiac toxicity should be done early in this process in order to identify high risk molecules early.

Mentions: The discovery and development of a new pharmaceutical drug requires more than a billion dollars and can take 12 years of research effort. The drug development process can be divided into four distinct phases: early discovery, late discovery, preclinical, and clinical. When a new chemical with interesting biological properties enters this process, it will undergo extensive testing designed to address and solve many complex issues (Fig. 1). New chemical entities or NCEs can be dropped from development for many reasons during this process, and the attrition rate for NCEs during preclinical and clinical studies is higher than it has been in decades. Although there are several factors that contribute to attrition, two major reasons are efficacy and toxicity (Fig.2). It has been estimated that only 1 of 10,000 chemicals that enter the discovery process ever reaches the market. This is not hard to imagine when one considers that 40% of NCEs that begin preclinical safety studies in animals will fail due to toxicity, and that 89% of NCEs that enter clinical trials will fail. The greatest cost in terms of time occurs in early and late discovery, which can require 6 to 8 years of research effort. In comparison, the highest cost in terms of dollars occurs in the preclinical and clinical studies. The ability to identify and reduce risk early can significantly improve the process of drug development by improving efficiency and improving the probability of success.


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)

Diagrammatic representation of the major steps in the drug discovery process. A typical path for drug discovery is presented. Compounds in a chemical library are screened to identify those molecules that interact with the intended target. Molecules that are positive in this assay “Hits” begin the process of lead identification (Hit-to-Lead) and Lead optimization. In Vitro toxicity screening as well as screens designed to identify ADME, genotoxicity, and cardiac toxicity should be done early in this process in order to identify high risk molecules early.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Diagrammatic representation of the major steps in the drug discovery process. A typical path for drug discovery is presented. Compounds in a chemical library are screened to identify those molecules that interact with the intended target. Molecules that are positive in this assay “Hits” begin the process of lead identification (Hit-to-Lead) and Lead optimization. In Vitro toxicity screening as well as screens designed to identify ADME, genotoxicity, and cardiac toxicity should be done early in this process in order to identify high risk molecules early.
Mentions: The discovery and development of a new pharmaceutical drug requires more than a billion dollars and can take 12 years of research effort. The drug development process can be divided into four distinct phases: early discovery, late discovery, preclinical, and clinical. When a new chemical with interesting biological properties enters this process, it will undergo extensive testing designed to address and solve many complex issues (Fig. 1). New chemical entities or NCEs can be dropped from development for many reasons during this process, and the attrition rate for NCEs during preclinical and clinical studies is higher than it has been in decades. Although there are several factors that contribute to attrition, two major reasons are efficacy and toxicity (Fig.2). It has been estimated that only 1 of 10,000 chemicals that enter the discovery process ever reaches the market. This is not hard to imagine when one considers that 40% of NCEs that begin preclinical safety studies in animals will fail due to toxicity, and that 89% of NCEs that enter clinical trials will fail. The greatest cost in terms of time occurs in early and late discovery, which can require 6 to 8 years of research effort. In comparison, the highest cost in terms of dollars occurs in the preclinical and clinical studies. The ability to identify and reduce risk early can significantly improve the process of drug development by improving efficiency and improving the probability of success.

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