Target organ toxicities in studies conducted to support first time in man dosing: An analysis across species and therapy areas

Horner, Steve; Ryan, David P.; Robinson, Sally; Callander, R.D.; Stamp, Katie; Roberts, Ruth

doi:10.1016/j.yrtph.2013.02.002

Cited by 36 publications

(21 citation statements)

References 14 publications

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“…This is especially important for the testis, which is 1 of the organs most frequently affected by candidate pharmaceuticals in toxicology studies in nonrodents (Horner et al 2013). Minipigs are a useful alternative to rabbits in reproductive and developmental toxicity studies and are being used increasingly in other toxicity studies.…”

Section: Introductionmentioning

confidence: 99%

Review of Sexual Maturity in the Minipig

Howroyd¹,

Peter

Rijk

2016

Toxicol Pathol

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It is important to know whether the animals used in toxicology studies are sexually mature. As minipigs are being used increasingly in toxicity studies, we reviewed published data on the age of sexual maturity in the minipig. Maturity in females was assessed on the basis either of normal cycles of progesterone secretion or of the histological presence of corpora lutea and, in males, was assessed on the histological appearance of the seminiferous tubules and epididymides. In female Gö ttingen minipigs, the first progesterone peak was at 3.7 to 4.2 or 6.1 to 6.5 months of age. These animals were in the presence of a boar. In female Gö ttingen minipigs in toxicology studies, which were not in the presence of a boar, at least 1 corpus luteum in the ovaries was present in only 50% of the females by 6.5 months of age, while all were mature by 7.7 months of age. Histological maturity in the male Yucatan minipig is reported to be attained at about 4.4 months old, but in male Göttingen minipigs at about 2 months old, although the definition of maturity may have been different in the 2 studies.

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Section: Introductionmentioning

confidence: 99%

Review of Sexual Maturity in the Minipig

Howroyd¹,

Peter

Rijk

2016

Toxicol Pathol

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“…The species used for small molecules are generally the rat and dog, 6 , 10 , 11 although the mouse, minipig, 12 NHP, and others can be used as alternatives when these are considered to be the more relevant species (with regard to pharmacological relevance, pharmacokinetic/metabolic profiles, and/or class-related tolerability/precedents). 6 The use of two phylogenetically unrelated animal species may increase the likelihood of detection of adverse effects in humans.…”

Section: Why Do We Use Two Species In Regulatory Toxicology Studies?mentioning

confidence: 99%

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

et al. 2018

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As part of the safety assessment of new drugs, the use of two species (a rodent and a nonrodent) for regulatory toxicology studies is the typical approach taken for small molecules. For biologics, species selection is dictated by pharmacological relevance, and single species toxicology packages (typically using the nonhuman primate) are common. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research and the Association of the British Pharmaceutical Industry are collaborating on a project to review the utility of two species in regulatory toxicology studies, with the aim to explore whether there are wider circumstances when data from a single species could be sufficient to enable safe progression in humans. An international working group consisting of 37 representatives from pharmaceutical and biotechnology companies, contract research organizations, academia, and regulatory bodies is coordinating a large-scale data sharing exercise to examine the potential for changes in current practice to reduce the number of species used for nonclinical safety testing at different stages of development. The challenge will be to determine whether two species toxicology adds significant value or whether in some instances data from a single species are sufficient (across a broader range of molecules than is currently the case) without compromising human safety.

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“…The species selected should be based on a pharmacokinetic and metabolism profile similar to humans and relevant pharmacology (i.e., the target has a similar role to that in humans), though for biologics, such as monoclonal antibodies (mAbs), species selection is usually based on the results of in vitro biological assays. The choice of species is generally the rat and dog ( Baldrick 2008 ; Horner et al 2013 ), although the minipig ( Colleton et al 2016 ) and nonhuman primate (NHP) are also used when relevant; the latter usually for biologics testing due to the highly specific human target ( Chapman et al 2009 ). Reviews of nonclinical data have shown that the nonrodent data identify additional toxicities to that detected in rodents, thus providing additional concordance and predictivity for adverse events identified in humans ( Horner et al 2013 ; Olson et al 2000 ; Tamaki et al 2013 ).…”

Section: Species Relevancementioning

confidence: 99%

“…The choice of species is generally the rat and dog ( Baldrick 2008 ; Horner et al 2013 ), although the minipig ( Colleton et al 2016 ) and nonhuman primate (NHP) are also used when relevant; the latter usually for biologics testing due to the highly specific human target ( Chapman et al 2009 ). Reviews of nonclinical data have shown that the nonrodent data identify additional toxicities to that detected in rodents, thus providing additional concordance and predictivity for adverse events identified in humans ( Horner et al 2013 ; Olson et al 2000 ; Tamaki et al 2013 ). However, with appropriate justification, it can be relevant for some packages (particularly for small molecules in areas with unmet medical need such as some cancers) to submit rodent-only data ( Newell et al 1999 ) ( ICH, S9 ) or chronic-dosing studies in a single rodent species for large molecules ( Chapman et al 2013 ) ( ICH, S6(R1) ).…”

Section: Species Relevancementioning

confidence: 99%

Opportunities to Apply the 3Rs in Safety Assessment Programs

Sewell

Edwards

Prior

et al. 2016

ILAR J

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Before a potential new medicine can be administered to humans it is essential that its safety is adequately assessed. Safety assessment in animals forms an integral part of this process, from early drug discovery and initial candidate selection to the program of recommended regulatory tests in animals. The 3Rs (replacement, reduction, and refinement of animals in research) are integrated in the current regulatory requirements and expectations and, in the EU, provide a legal and ethical framework for in vivo research to ensure the scientific objectives are met whilst minimizing animal use and maintaining high animal welfare standards. Though the regulations are designed to uncover potential risks, they are intended to be flexible, so that the most appropriate approach can be taken for an individual product. This article outlines current and future opportunities to apply the 3Rs in safety assessment programs for pharmaceuticals, and the potential (scientific, financial, and ethical) benefits to the industry, across the drug discovery and development process. For example, improvements to, or the development of, novel, early screens (e.g., in vitro, in silico, or nonmammalian screens) designed to identify compounds with undesirable characteristics earlier in development have the potential to reduce late-stage attrition by improving the selection of compounds that require regulatory testing in animals. Opportunities also exist within the current regulatory framework to simultaneously reduce and/or refine animal use and improve scientific outcomes through improvements to technical procedures and/or adjustments to study designs. It is important that approaches to safety assessment are continuously reviewed and challenged to ensure they are science-driven and predictive of relevant effects in humans.

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Target organ toxicities in studies conducted to support first time in man dosing: An analysis across species and therapy areas

Cited by 36 publications

References 14 publications

Review of Sexual Maturity in the Minipig

Review of Sexual Maturity in the Minipig

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

Opportunities to Apply the 3Rs in Safety Assessment Programs

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