Commentary on “Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

Long, Gerald G.

doi:10.1177/0192623309359795

Cited by 2 publications

(1 citation statement)

References 19 publications

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“…There is no question that the work done by Nova Nordisk to date was effective in providing a path forward for this class of therapeutics. However, additional understanding of the mechanism of action of rodent C-cell proliferation is required to understand the relative risk to humans (Long 2010).…”

mentioning

confidence: 99%

On-target and Off-target-based Toxicologic Effects

Rudmann

2012

Toxicol Pathol

113

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Adverse toxicologic effects are categorized as chemical-based, on-target, or off-target effects. Chemical-based toxicity is defined as toxicity that is related to the physicochemical characteristics of a compound and its effects on cellular organelles, membranes, and/or metabolic pathways. On-target refers to exaggerated and adverse pharmacologic effects at the target of interest in the test system. Off-target refers to adverse effects as a result of modulation of other targets; these may be related biologically or totally unrelated to the target of interest. Both the risk assessment and development strategies used for xenobiotics are influenced by the understanding of the mechanism of toxicity. It is imperative that the toxicologic pathologist use the toxicologic and biologic data at hand and literature information on the target to form testable hypotheses related to whether a toxicity is chemical-based, on-target, or off-target. The objective of this session at the 2012 Society of Toxicologic Pathologists Symposium in Boston, Massachusetts, was to discuss chemical-based, on-target, and off-target-based effects and the scientific approaches used to aid in their human risk assessment.

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confidence: 99%

On-target and Off-target-based Toxicologic Effects

Rudmann

2012

Toxicol Pathol

113

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Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

Reynolds

Abernathy

Baracani

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Nonclinical safety assessment is an essential component of drug discovery and development. Early in the drug discovery/development continuum, there are no regulatory guidelines and sponsors typically harness a range of in silico , in vitro , and short‐term in vivo toxicology screens and pilot studies to develop comparative toxicity profiles for compounds under consideration. Results from these early evaluations can be used to terminate the development of compounds with undesirable toxicity liabilities as well as to prioritize other compounds for further evaluation. As drug candidate molecules approach entry into clinical trials, regulatory expectations regarding nonclinical safety assessment become more explicit. Scientists in the pharmaceutical industry have worked with their regulatory counterparts to establish an organizational structure – the International Conference on Harmonisation (ICH) – to develop internationally accepted guidelines that specify requirements for nonclinical safety assessment activities in a phase‐specific manner. The ICH guidelines cover the need for repeat‐dose toxicology studies of increasing duration in rodents and nonrodents, safety pharmacology studies, genetic toxicity tests, immunotoxicity and immunogenicity evaluations, phototoxicity assessments, developmental and reproductive toxicity studies, and carcinogenicity assessments. In planning, conducting, and reporting these studies, the toxicologist must ensure that a fully integrated assessment of potential safety liabilities associated with the test drug is communicated to the development team so that potential safety concerns can be properly addressed.

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Commentary on “Evaluation of Possible Carcinogenic Risk to Humans Based on Liver Tumors in Rodent Assays

Cited by 2 publications

References 19 publications

On-target and Off-target-based Toxicologic Effects

On-target and Off-target-based Toxicologic Effects

Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

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