Safety Assessment of Pharmaceuticals: Examples of Inadequate Assessments and a Mechanistic Approach to Assuring Adequate Assessment

Williams, Gary M.

doi:10.1177/019262339702500108

Cited by 5 publications

(6 citation statements)

References 43 publications

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“…Rat hepatocytes cultured on Matrigel ® in chemically defined media are useful systems for identifying and characterizing genes that are differentially expressed in response to exposure of carcinogens, especially compounds such as phenobarbital, DDT, estradiol, and diethylstilbestrol, which have been reported to exert carcinogenic effects through an epigenetic mechanism (96,97). In addition, hepatocytes cultured under these conditions respond to prototypical metabolizing enzyme inducers such as 3-methylcholanthrene, hydrocortisone, and clofibrate in a similar fashion to rats exposed to these or comparable prototypical liver enzyme inducers (92).…”

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

“…Another short-term in vitro test to investigate carcinogens using hepatocytes is the DNA repair assay (96,97,106). This assay utilizes the metabolic capability of the liver and the specificity of the DNA repair as an indicator of DNA damage.…”

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

“…This assay distinguishes genotoxic from nongenotoxic chemicals of a wide variety of structural classes and is sometimes included as a part of the battery tests in the Tier II testing strategy to screen compounds as potential carcinogens. The DNA repair assay has proven to be sensitive and reliable with agents that require metabolic activation, including some not readily detected by other systems (96).…”

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

“…Moreover, the induction of prolonged cell proliferation has also been suggested as a mechanism of nongenotoxic carcinogens. The use of CHO cells and the 5-bromo-2-deoxyuridine (BrdUrd) labeling probe has shown to be especially useful in assessing chemically induced cell proliferation (96,97,109).…”

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

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Predictive Value of in Vitro Model Systems in Toxicology

Dávila¹,

Rodriguez

Melchert

et al. 1998

Annu. Rev. Pharmacol. Toxicol.

120

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The application of in vitro model systems to evaluate the toxicity of xenobiotics has significantly enhanced our understanding of drug- and chemical-induced target toxicity. From a scientific perspective, there are several reasons for the popularity of in vitro model systems. From the public perspective, in vitro model systems enjoy increasing popularity because their application may allow a reduction in the number of live animals employed in toxicity testing. In this review, we present an overview of the use of in vitro model systems to investigate target organ toxicity of drugs and chemicals, and provide selective examples of these model systems to better understand cutaneous and ocular toxicity and the role of drug metabolism in the hepatotoxicity of selected agents. We conclude by examining the value and use of in vitro model systems in industrial development of new pharmaceutical agents.

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Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

Section: Primary Adult Rat Hepatocytes As Predictive In Vitro Model Fmentioning

confidence: 99%

See 2 more Smart Citations

Predictive Value of in Vitro Model Systems in Toxicology

Dávila¹,

Rodriguez

Melchert

et al. 1998

Annu. Rev. Pharmacol. Toxicol.

120

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“…Is this finding insignificant or the first sign of a major issue? A lot can go wrong at this point 37 including e.g. ignoring the finding as not significant or becoming hyperactive.…”

Section: Introduction and Overviewmentioning

confidence: 99%

Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Ettlin¹,

Kuroda

Plassmann³

et al. 2010

J Toxicol Pathol

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Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail.

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