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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

In vitro toxicity screening data combined with clinical data show good concordance. In this experiment, 150 approved drugs were selected and analyzed in a blinded manner. The aim of the study was to determine the relationship between the estimated plasma concentration where toxicity would be expected to occur in rat 14-d repeat dose studies (Ctox), and the maximum therapeutic plasma concentration (MTPC) achieved during the course of therapy in humans. The diagonal red line represents the threshold of toxicity where the estimated plasma concentration for toxicity is equal to the maximum plasma concentration measured in humans. If the Ctox value has any relationship to MTPC, most approved drugs should not exceed this threshold value. The data above indicate that 97% of the approved drugs do not achieve plasma concentrations equal to or greater than the predicted level of toxicity. If the drugs tested had been screened for toxicity early in their discovery life-cycle, those that had estimated plasma concentrations for toxicity that fell below 20 µM would have been flagged as toxic. The horizontal red line depicts this point on the graph. Most of the approved drugs are above this line, however some fall below, and therefore might be considered false positives in the in vitro screen. Upon closer inspection, these compounds all have been associated with toxicity in human patients. The key to why these drugs are still used in the clinic is related to their potency, in vitro margin of safety, and risk/benefit analysis. It is clear that as drug plasma concentrations approach the threshold value (Ctox) of toxicity the probability of an adverse event increases. This graph was developed by Dr. Georgor Zlokarnik and the work was part of a collaborative research project between CeeTox, Inc. and Vertex Pharmaceuticals.
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Figure 15: In vitro toxicity screening data combined with clinical data show good concordance. In this experiment, 150 approved drugs were selected and analyzed in a blinded manner. The aim of the study was to determine the relationship between the estimated plasma concentration where toxicity would be expected to occur in rat 14-d repeat dose studies (Ctox), and the maximum therapeutic plasma concentration (MTPC) achieved during the course of therapy in humans. The diagonal red line represents the threshold of toxicity where the estimated plasma concentration for toxicity is equal to the maximum plasma concentration measured in humans. If the Ctox value has any relationship to MTPC, most approved drugs should not exceed this threshold value. The data above indicate that 97% of the approved drugs do not achieve plasma concentrations equal to or greater than the predicted level of toxicity. If the drugs tested had been screened for toxicity early in their discovery life-cycle, those that had estimated plasma concentrations for toxicity that fell below 20 µM would have been flagged as toxic. The horizontal red line depicts this point on the graph. Most of the approved drugs are above this line, however some fall below, and therefore might be considered false positives in the in vitro screen. Upon closer inspection, these compounds all have been associated with toxicity in human patients. The key to why these drugs are still used in the clinic is related to their potency, in vitro margin of safety, and risk/benefit analysis. It is clear that as drug plasma concentrations approach the threshold value (Ctox) of toxicity the probability of an adverse event increases. This graph was developed by Dr. Georgor Zlokarnik and the work was part of a collaborative research project between CeeTox, Inc. and Vertex Pharmaceuticals.

Mentions: In the study depicted in Fig. (15), 150 approved drugs were selected by a third party and presented in a blinded manner for evaluation in a panel of biochemical assays (CeeTox Panel®). The intent of this study was to compare an estimated plasma concentration (Ctox) where toxicity would be expected to occur in rat 14-day repaeat dose studies, derived from the in vitro data, to the maximum therapeutic plasma concentration (MTPC) achieved during the course of therapy in the clinic. The diagonal red line depicts the point where the predicted toxicity value (Ctox) is equal to the MTPC. Most approved drugs should not reach plasma concentrations that are greater than this predicted threshold for toxicity. Clearly, most of the drugs (97%) fall to the left of this line. Those compounds that have MTPCs that meet or exceed this line of equivalence are in some cases drugs that are known to cause toxicity under therapeutic conditions, such as azathioprine. What about false positives? If the drugs in Fig. (15) had been evaluated in an in vitro toxicity screening program early in the drug discovery process those with predicted toxicity values (Ctox) of 20 µM or less would have been considered to have a high probability of causing toxicity in animal studies. As expected the majority of approved drugs have estimated toxicity values greater than 20 µM. However, some would have been identified as toxic by the in vitro system (Fig. 15, red circle). Unmasking some of these molecules reveals that an important factor to be considered for continued development of NCEs lies in the intended use of the drug (risk/benefit), its potency, and, margin of safety.


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)

In vitro toxicity screening data combined with clinical data show good concordance. In this experiment, 150 approved drugs were selected and analyzed in a blinded manner. The aim of the study was to determine the relationship between the estimated plasma concentration where toxicity would be expected to occur in rat 14-d repeat dose studies (Ctox), and the maximum therapeutic plasma concentration (MTPC) achieved during the course of therapy in humans. The diagonal red line represents the threshold of toxicity where the estimated plasma concentration for toxicity is equal to the maximum plasma concentration measured in humans. If the Ctox value has any relationship to MTPC, most approved drugs should not exceed this threshold value. The data above indicate that 97% of the approved drugs do not achieve plasma concentrations equal to or greater than the predicted level of toxicity. If the drugs tested had been screened for toxicity early in their discovery life-cycle, those that had estimated plasma concentrations for toxicity that fell below 20 µM would have been flagged as toxic. The horizontal red line depicts this point on the graph. Most of the approved drugs are above this line, however some fall below, and therefore might be considered false positives in the in vitro screen. Upon closer inspection, these compounds all have been associated with toxicity in human patients. The key to why these drugs are still used in the clinic is related to their potency, in vitro margin of safety, and risk/benefit analysis. It is clear that as drug plasma concentrations approach the threshold value (Ctox) of toxicity the probability of an adverse event increases. This graph was developed by Dr. Georgor Zlokarnik and the work was part of a collaborative research project between CeeTox, Inc. and Vertex Pharmaceuticals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 15: In vitro toxicity screening data combined with clinical data show good concordance. In this experiment, 150 approved drugs were selected and analyzed in a blinded manner. The aim of the study was to determine the relationship between the estimated plasma concentration where toxicity would be expected to occur in rat 14-d repeat dose studies (Ctox), and the maximum therapeutic plasma concentration (MTPC) achieved during the course of therapy in humans. The diagonal red line represents the threshold of toxicity where the estimated plasma concentration for toxicity is equal to the maximum plasma concentration measured in humans. If the Ctox value has any relationship to MTPC, most approved drugs should not exceed this threshold value. The data above indicate that 97% of the approved drugs do not achieve plasma concentrations equal to or greater than the predicted level of toxicity. If the drugs tested had been screened for toxicity early in their discovery life-cycle, those that had estimated plasma concentrations for toxicity that fell below 20 µM would have been flagged as toxic. The horizontal red line depicts this point on the graph. Most of the approved drugs are above this line, however some fall below, and therefore might be considered false positives in the in vitro screen. Upon closer inspection, these compounds all have been associated with toxicity in human patients. The key to why these drugs are still used in the clinic is related to their potency, in vitro margin of safety, and risk/benefit analysis. It is clear that as drug plasma concentrations approach the threshold value (Ctox) of toxicity the probability of an adverse event increases. This graph was developed by Dr. Georgor Zlokarnik and the work was part of a collaborative research project between CeeTox, Inc. and Vertex Pharmaceuticals.
Mentions: In the study depicted in Fig. (15), 150 approved drugs were selected by a third party and presented in a blinded manner for evaluation in a panel of biochemical assays (CeeTox Panel®). The intent of this study was to compare an estimated plasma concentration (Ctox) where toxicity would be expected to occur in rat 14-day repaeat dose studies, derived from the in vitro data, to the maximum therapeutic plasma concentration (MTPC) achieved during the course of therapy in the clinic. The diagonal red line depicts the point where the predicted toxicity value (Ctox) is equal to the MTPC. Most approved drugs should not reach plasma concentrations that are greater than this predicted threshold for toxicity. Clearly, most of the drugs (97%) fall to the left of this line. Those compounds that have MTPCs that meet or exceed this line of equivalence are in some cases drugs that are known to cause toxicity under therapeutic conditions, such as azathioprine. What about false positives? If the drugs in Fig. (15) had been evaluated in an in vitro toxicity screening program early in the drug discovery process those with predicted toxicity values (Ctox) of 20 µM or less would have been considered to have a high probability of causing toxicity in animal studies. As expected the majority of approved drugs have estimated toxicity values greater than 20 µM. However, some would have been identified as toxic by the in vitro system (Fig. 15, red circle). Unmasking some of these molecules reveals that an important factor to be considered for continued development of NCEs lies in the intended use of the drug (risk/benefit), its potency, and, margin of safety.

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