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Neurofunctional test batteries in safety pharmacology – Current and emerging considerations for the drug development process

Jackson, Samual J and Authier, Simon and Brohmann, Henning and Goody, Susan MG and Jones, David and Prior, Helen and Rosch, Anke and Traebert, Martin and Tse, Karen and Valentin, Jean Pierre and Milne, Aileen (2019) Neurofunctional test batteries in safety pharmacology – Current and emerging considerations for the drug development process. Journal of pharmacological and toxicological methods, 100. ISSN 10568719

Abstract

Regulatory guidelines recommend specialised safety pharmacology assessments in animals to characterise drug-induced effects on the central nervous system (CNS) prior to first-in-human trials, including the functional observational battery or Irwin test (here collectively termed neurofunctional assessments). These assessments effectively detect overtly neurotoxic drugs; however, the suitability of the in vivo assessments to readily detect more subtle drug effects on the nervous system has been questioned. A survey was formulated by an international expert working group convened by the (NC3Rs) to capture practice in CNS neurofunctional assessment tests and opinions on the perceived impact of in vivo test battery endpoints. Impact was defined as “the impact of measures alone/in combination on decision making in drug development or candidate selection when using the neurofunctional assessment”. The results demonstrate that rodents are predominantly used for small molecule assessments, whereas non-rodents are frequently used to test biotherapeutics. Practice varied between respondents in terms of experimental design. Subsets of test battery endpoints were consistently considered highly impactful (e.g. convulsions, stereotypic behaviors); however, the perceived impact level of other endpoints varied depending whether drugs were designed for CNS targets. Many endpoints were considered to have no or minimal impact, whereas a subset of endpoints in CNS test batteries appears more impactful than others. A critical evaluation is required to assess whether the translational value of CNS in vivo safety pharmacology assessments could be increased by modifying or augmenting standard CNS test batteries. A revised approach to CNS safety assessment has the potential to reduce animal numbers without compromising patient safety.

Item Type: Article
Keywords: Animal Central Nervous System Functional observational battery Irwin test Methods Neurofunctional assessment Patient safety Reduction Safety pharmacology Test battery endpoints
Date Deposited: 24 Sep 2019 00:45
Last Modified: 24 Sep 2019 00:45
URI: https://oak.novartis.com/id/eprint/39747

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