Variability of non-clinical behavioral CNS safety assessment: An intercompany comparison

Himmel, Herbert M.; Irwin,; Delaunois, Annie; Deurinck, Mark; Dinklo, Theo; Faelker, Therese M. Eriksson; Habermann, Christopher; Heers, Cara; Hempel, K; Lorenz, Helga; Rosch, Anke; Schauerte, Heike; Teuns, Greet; Traebert, Martin; Amsterdam, Christoph van; Linde, Henk van der

doi:10.1016/j.vascn.2019.03.002

Cited by 10 publications

(15 citation statements)

References 30 publications

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“…It has already been emphasized that variability observed in Irwin and FOB testing may question the overall validity of information obtained in preclinical rodent safety assessments (24)(25)(26). In particular, the FOB/Irwin test used, the applied scoring system, and the level of experience and/or training of investigators can profoundly affect the comparability of study results (24). Also, environmental and experimental factors have been considered key factors confounding the robustness of FOB/Irwin tests (24,27,28).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, thorough education and adequate training of test examiners is crucial. A recent study has evaluated the impact of partial standardization focussed on a standard dose, administration route, and time points on Irwin/FOB data obtained by testing two drugs in male Wistar rats based on laboratory-specific scoring protocols (24). The authors reported that their partial standardization did not result in a relevant reduction in quantitative variability.…”

Section: Introductionmentioning

confidence: 99%

“…To allow comparability with two other subprojects of the EQIPD consortium that focused on an open field paradigm (11) and pharmaco-EEG, the study was performed in mice, representing the second most common species for Irwin/FOB testing (16, 24). MK-801 was chosen as the compound, considering its broad range of effects on various parameters from different functional domains assessed in the Irwin test.…”

Section: Introductionmentioning

confidence: 99%

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A Systematic Assessment of Robustness in CNS Safety Pharmacology

Reiber,

Stirling,

Ahuis

et al. 2024

Preprint

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Irwin tests are key preclinical study elements for characterizing drug-induced neurological side effects. This multicenter study aimed to assess the robustness of Irwin tests across multinational sites during three stages of protocol harmonization. The projects were part of the EQIPD framework (Enhanced Quality in Preclinical Data, https://quality-preclinical-data.eu/), aiming to increase success rates in transition from preclinical testing to clinical application. Female and male NMRI mice were assigned to one of three groups (vehicle, 0.1 mg/kg MK-801, 0.3 mg/kg MK-801). Irwin scores were assessed at baseline and multiple times following injection of MK-801, a non-competitive NMDA antagonist, using local protocols (stage 1), a shared protocol with harmonized environmental design (stage 2), and fully harmonized Irwin scoring protocols (stage 3). The analysis based on the four functional domains (motor, autonomic, sedation, and excitation) revealed substantial data variability in stages 1 and 2. Although there was still marked overall heterogeneity between sites in stage 3 after complete harmonization of the Irwin scoring scheme, heterogeneity was only moderate within functional domains. When comparing treatment groups vs. vehicle, we found large effect sizes in the motor domain and subtle to moderate effects in the excitation-related and autonomic domain. The pronounced interlaboratory variability in Irwin datasets for the CNS-active compound MK-801 needs to be carefully considered by companies and experimenters when making decisions during drug development. While environmental and general study design had a minor impact, the study suggests that harmonization of parameters and their scoring can limit variability and increase robustness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Systematic Assessment of Robustness in CNS Safety Pharmacology

Reiber,

Stirling,

Ahuis

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…In one study, a specific FOB protocol and locomotor activity was used to test known neurotoxicants across laboratories (Moser et al., 1997). Other more recent reports have compared FOB and/or Irwin data across studies with multiple drugs, both within and across a number of pharmaceutical companies (Himmel et al., 2019; Redfern et al., 2019). In all these comparative studies, the results showed that the methods were adequate to detect behavioral effects of known CNS molecules.…”

Section: Commentarymentioning

confidence: 99%

The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents

Mathiasen

Moser

2023

Current Protocols

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The modified Irwin procedure or functional observational battery (FOB) can be used to achieve several goals. New chemical entities (NCEs) can be behaviorally screened for nervous system effects at a variety of doses to identify potential therapeutic uses and in the selection of appropriate doses for subsequent assays. NCEs can also be evaluated in the behavioral battery and compared with reference standards to assess liabilities in a new compound class, with an estimated therapeutic index being suggested by the doses used in comparison to therapeutic doses. For the assessment of neurotoxicology, the FOB is often used. The differences between the two assays are subtle. The procedures used are essentially the same, but when considering neurotoxicology, the FOB is often conducted using GLP guidelines, with more animals being used per group, and doses that are low enough to determine a no effect level and high enough to induce marked nervous system behaviors. © 2023 Wiley Periodicals LLC. Basic Protocol: The Irwin test and FOB for assessing the effects of compounds on behavior, physiology, and safety pharmacology in rodents

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“…В частности, у крыс такими эффектами являются рефлекс Штрауба, вертикализация, а также, по данным некоторых авторов, пилоэрекция [22]. Таким образом, проблема экстраполяции нейротоксических эффектов далека от решения, что не позволяет однозначно прогнозировать возможные нежелательные реакции у человека [23]. Недостатком тестов Ирвина и НФТ является невозможность оценки вкусовых, зрительных, обонятельных и слуховых дисфункций, изменений в структуре сна, а также когнитивных нарушений.…”

Section: набор функциональных тестов и тесты ирвина применительно к задачам доклинических исследований безопасностиunclassified

Preclinical in vivo Neurotoxicity Studies of Drug Candidates

Еремина

Колик

Ostrovskaia

et al. 2020

Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo pr

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Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.

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Variability of non-clinical behavioral CNS safety assessment: An intercompany comparison

Cited by 10 publications

References 30 publications

A Systematic Assessment of Robustness in CNS Safety Pharmacology

A Systematic Assessment of Robustness in CNS Safety Pharmacology

The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents

Preclinical in vivo Neurotoxicity Studies of Drug Candidates

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