Limits...
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.

Show MeSH

Related in: MedlinePlus

In vitro toxicity profile for terfenadine, an example of afalse positive. Terfenadine produced significant toxicity at both 6and 24 h. If this compound had been evaluated in an early discoveryprogram, the in vitro data would have indicated toxicity. Thiscompound was successful in all IND enabling studies. The reasonfor the low levels of toxicity measured in vivo is first-passmetabolism. Terfenadine has a bioavailability of <1% andundergoes first-pass metabolism. Thus, in vivo plasmaconcentrations of parent drug are below toxic levels. In vitro, wheremetabolism is low, parent compound can reach concentrations thatcan produce toxicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2908937&req=5

Figure 10: In vitro toxicity profile for terfenadine, an example of afalse positive. Terfenadine produced significant toxicity at both 6and 24 h. If this compound had been evaluated in an early discoveryprogram, the in vitro data would have indicated toxicity. Thiscompound was successful in all IND enabling studies. The reasonfor the low levels of toxicity measured in vivo is first-passmetabolism. Terfenadine has a bioavailability of <1% andundergoes first-pass metabolism. Thus, in vivo plasmaconcentrations of parent drug are below toxic levels. In vitro, wheremetabolism is low, parent compound can reach concentrations thatcan produce toxicity.

Mentions: In order for in vitro toxicity data to be used in the decision making process, it must be complete, mechanism-based, and reliable with a low incidence of false positive and false negative results. Again, in vitro and in vivo reference points can greatly improve the predictive power. Terfenadine was marketed as seldane, an antihistamine that would not cause drowsiness. In January of 1997 the FDA proposed removing terfenadine from the market because of potentially fatal cardiac effects observed in patients who were also receiving other commonly prescribed medications, including antifungal agents in the azole class, such as ketoconazole. The cardiac toxicity was the result of a drug-drug interaction with compounds that have been shown to be potent mechanism-based inhibitors of cytochrome P450 (CYP) metabolizing enzymes (reviewed by [59]). When terfenadine was evaluated in an in vitro model over an exposure concentration range of 0 to 300 µM for 6 and 24 h, significant toxicity was observed (Fig. 10). These data indicate that if terfenadine had been evaluated in early discovery with an in vitro toxicity model, it might have been identified as having substantial toxicity. However, this drug made it to market; it passed the preclinical safety studies and clinical trials, but caused significant cytotoxicity in vitro, a false positive result.


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 profile for terfenadine, an example of afalse positive. Terfenadine produced significant toxicity at both 6and 24 h. If this compound had been evaluated in an early discoveryprogram, the in vitro data would have indicated toxicity. Thiscompound was successful in all IND enabling studies. The reasonfor the low levels of toxicity measured in vivo is first-passmetabolism. Terfenadine has a bioavailability of <1% andundergoes first-pass metabolism. Thus, in vivo plasmaconcentrations of parent drug are below toxic levels. In vitro, wheremetabolism is low, parent compound can reach concentrations thatcan produce toxicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 10: In vitro toxicity profile for terfenadine, an example of afalse positive. Terfenadine produced significant toxicity at both 6and 24 h. If this compound had been evaluated in an early discoveryprogram, the in vitro data would have indicated toxicity. Thiscompound was successful in all IND enabling studies. The reasonfor the low levels of toxicity measured in vivo is first-passmetabolism. Terfenadine has a bioavailability of <1% andundergoes first-pass metabolism. Thus, in vivo plasmaconcentrations of parent drug are below toxic levels. In vitro, wheremetabolism is low, parent compound can reach concentrations thatcan produce toxicity.
Mentions: In order for in vitro toxicity data to be used in the decision making process, it must be complete, mechanism-based, and reliable with a low incidence of false positive and false negative results. Again, in vitro and in vivo reference points can greatly improve the predictive power. Terfenadine was marketed as seldane, an antihistamine that would not cause drowsiness. In January of 1997 the FDA proposed removing terfenadine from the market because of potentially fatal cardiac effects observed in patients who were also receiving other commonly prescribed medications, including antifungal agents in the azole class, such as ketoconazole. The cardiac toxicity was the result of a drug-drug interaction with compounds that have been shown to be potent mechanism-based inhibitors of cytochrome P450 (CYP) metabolizing enzymes (reviewed by [59]). When terfenadine was evaluated in an in vitro model over an exposure concentration range of 0 to 300 µM for 6 and 24 h, significant toxicity was observed (Fig. 10). These data indicate that if terfenadine had been evaluated in early discovery with an in vitro toxicity model, it might have been identified as having substantial toxicity. However, this drug made it to market; it passed the preclinical safety studies and clinical trials, but caused significant cytotoxicity in vitro, a false positive result.

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