A systematic assessment of robustness in CNS safety pharmacology.

Autor: Reiber M; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany., Stirling H; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany., Ahuis TP; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Arias W; PsychoGenics, Inc., Paramus, New Jersey, USA., Aulehner K; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany., Dreßler U; AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany., Kas MJH; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands., Kela J; Orion Corporation, Turku, Finland., Kerker K; PsychoGenics, Inc., Paramus, New Jersey, USA., Kuosmanen T; Orion Corporation, Turku, Finland., Lorenz H; AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany., Pennington AT; PsychoGenics, Inc., Paramus, New Jersey, USA., von Rüden EL; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany., Schauerte H; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Seiffert I; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany., Talbot SR; Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany., Torturo C; PsychoGenics, Inc., Paramus, New Jersey, USA., Virtanen S; Orion Corporation, Turku, Finland., Waldron AM; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany., Ramboz S; PsychoGenics, Inc., Paramus, New Jersey, USA., Potschka H; Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Oct 10. Date of Electronic Publication: 2024 Oct 10.
DOI: 10.1111/bph.17358
Abstrakt: Background and Purpose: Irwin tests are key preclinical study elements for characterising drug-induced neurological side effects. This multicentre study aimed to assess the robustness of Irwin tests across multinational sites during three stages of protocol harmonisation. The projects were part of the Enhanced Quality in Preclinical Data framework, aiming to increase success rates in transition from preclinical testing to clinical application.
Experimental Approach: Female and male NMRI mice were assigned to one of three groups (vehicle, MK-801 0.1 and 0.3 mg kg -1 ). Irwin scores were assessed at baseline and multiple times following intraperitoneal injection of MK-801 using local protocols (Stage 1), shared protocols with harmonised environmental design (Stage 2) and fully harmonised Irwin scoring protocols (Stage 3).
Key Results: 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 harmonisation of the Irwin scoring scheme, heterogeneity was only moderate within functional domains. When comparing treatment groups versus vehicle, we found large effect sizes in the motor domain and subtle to moderate effects in the excitation-related and autonomic domains.
Conclusion and Implications: The pronounced interlaboratory variability in Irwin datasets for the CNS-active compound MK-801 needs to be carefully considered when making decisions during drug development. While environmental and general study design had a minor impact, the study suggests that harmonisation of parameters and their scoring can limit variability and increase robustness.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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