Reproductive and developmental safety evaluation of new pharmaceutical compounds

Garg, Ramesh C.; Bracken, William M.; Hoberman, Alan M.

doi:10.1016/b978-0-12-382032-7.10008-6

Cited by 9 publications

(12 citation statements)

References 83 publications

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“…However, this assumption, although based on experimental observations, is not necessarily always true (EPA, 1991). The classification of a substance as a human hazard only indicates risk of teratogenesis to humans, and even if that substance can actually invoke teratogenic responses in humans, these responses may be different to those shown in animal models (Garg et al, 2011). The same teratogen may invoke different responses in different species, strains, and even sub-strains, which complicates extrapolation of the conclusions obtained from animal assays to humans and limits the reliability of risk assessment studies.…”

Section: Difficulties In the Extrapolation Of Toxicity Information Be...mentioning

confidence: 99%

“…Probably the most well-known example of a teratogen with species-specific effects is thalidomide, as it influenced greatly the official protocols currently employed to assess developmental toxicity (Garg et al, 2011;Vargesson, 2013;2015). Thalidomide was a drug prescribed in the late 1950s to treat morning sickness associated with pregnancy which was later proved to cause serious teratological effects and increase the rates of miscarriages and infant mortality.…”

Section: Difficulties In the Extrapolation Of Toxicity Information Be...mentioning

confidence: 99%

“…Interspecies differences regarding embryonic development, metabolic pathways or placentation may cause different toxicity responses across species and should be considered when extrapolating data obtained from animal models to humans (EPA, 1991;Garg et al, 2011). The genetic background of each species is also an important consideration.…”

Section: Difficulties In the Extrapolation Of Toxicity Information Be...mentioning

confidence: 99%

“…Therefore, the information obtained from the rat, even if employed along with the information obtained from other models, is used to make decisions about the potential risk of a specific substance to humans, and, consequently, about the marketability of that substance. These assessment studies assume that a substance that causes a teratogenic response in rats implies a risk of developmental toxicity to humans (EPA, 1991;Garg et al, 2011). In turn, the potential response that this substance may invoke in humans is assumed to resemble in some degree the response observed in rats, which is supported by experimental data and by the conservation of most biological processes in humans and rats, including developmental processes such as palatogenesis (Coleman, 1965;Ferguson, 1978;EPA, 1991;Yoon et al, 2000;Leung et al, 2017).…”

Section: Aims and Objectives: Evaluating Developmental Toxicity In Th...mentioning

confidence: 99%

“…However, the evidence to support the assumption that rats and humans have conserved toxic responses is limited, and extrapolation of relevant data for risk assessment from animals to humans is complex (EPA, 1991). As a consequence of these difficulties, a substance may be wrongly classified as harmful to humans because of the results of a risk assessment test, causing an unnecessary waste of resources and avoiding the commercialisation of a safe and useful substance (Tuomisto, 2004;Garg et al, 2011).…”

Section: Aims and Objectives: Evaluating Developmental Toxicity In Th...mentioning

confidence: 99%

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Evaluating developmental toxicity in the rat as a basis for human risk assessment for cleft palate

et al. 2014

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Section: Difficulties In the Extrapolation Of Toxicity Information Be...mentioning

confidence: 99%

Section: Difficulties In the Extrapolation Of Toxicity Information Be...mentioning

confidence: 99%

Section: Difficulties In the Extrapolation Of Toxicity Information Be...mentioning

confidence: 99%

Section: Aims and Objectives: Evaluating Developmental Toxicity In Th...mentioning

confidence: 99%

Section: Aims and Objectives: Evaluating Developmental Toxicity In Th...mentioning

confidence: 99%

See 3 more Smart Citations

Evaluating developmental toxicity in the rat as a basis for human risk assessment for cleft palate

et al. 2014

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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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Microfluidic Multitissue Platform for Advanced Embryotoxicity Testing In Vitro

et al. 2019

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The integration of metabolic competence in developmental toxicity assays in vitro is of fundamental importance to better predict adverse drug effects. Here, a microfluidic hanging‐drop platform is presented that seamlessly integrates liver metabolism into the embryonic stem cell test (EST). Primary human liver microtissues (hLiMTs) and embryoid bodies (EBs) are combined in the same fluidic network, so that hLiMT‐generated metabolites are directly transported to the EBs. Gravity‐driven flow through the network enables continuous intertissue communication, constant medium turnover, and, most importantly, immediate exchange of metabolites. As a proof of concept, the prodrug cyclophosphamide is investigated and a fourfold lower ID50 concentration (50% inhibition of EB differentiation) is found after biotransformation, which demonstrates the potentially adverse effects of metabolites on embryotoxicity. The metaEST platform provides a promising tool to increase the predictive power of the current EST assay by more comprehensively including and better reflecting physiological processes in in vitro tests.

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Reproductive and developmental safety evaluation of new pharmaceutical compounds

Cited by 9 publications

References 83 publications

Evaluating developmental toxicity in the rat as a basis for human risk assessment for cleft palate

Evaluating developmental toxicity in the rat as a basis for human risk assessment for cleft palate

Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

Microfluidic Multitissue Platform for Advanced Embryotoxicity Testing In Vitro

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