A systematic assessment of robustness in CNS safety pharmacology.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Maria Reiber, Helen Stirling, Tim P Ahuis, Washington Arias, Katharina Aulehner, Ute Dreßler, Martien J H Kas, Johanna Kela, Kimberly Kerker, Tarja Kuosmanen, Helga Lorenz, Alexander T Pennington, Eva-Lotta von Rüden, Heike Schauerte, Isabel Seiffert, Steven R Talbot, Christina Torturo, Sami Virtanen, Ann-Marie Waldron, Sylvie Ramboz, Heidrun Potschka
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Abstract

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.

系统评估中枢神经系统安全药理学的稳健性。
背景和目的:Irwin 试验是临床前研究中描述药物引起的神经系统副作用的关键要素。这项多中心研究旨在评估跨国研究机构在方案协调的三个阶段中Irwin试验的稳健性。这些项目是提高临床前数据质量框架的一部分,旨在提高从临床前试验过渡到临床应用的成功率:实验方法:将雌性和雄性 NMRI 小鼠分为三组(载体、MK-801 0.1 和 0.3 mg kg-1)。实验方法:雌性和雄性 NMRI 小鼠被分配到三个组中(车辆组、MK-801 0.1 和 0.3 mg kg-1),在基线和腹腔注射 MK-801 后多次使用本地方案(第 1 阶段)、具有统一环境设计的共享方案(第 2 阶段)和完全统一的 Irwin 评分方案(第 3 阶段)评估 Irwin 评分:主要结果:基于四个功能领域(运动、自主神经、镇静和兴奋)的分析表明,第 1 和第 2 阶段的数据差异很大。虽然在完全统一了 Irwin 评分标准后,第 3 阶段的研究地点之间仍存在明显的总体异质性,但功能域内的异质性仅为中等。在比较治疗组与载体时,我们发现在运动领域有较大的效应大小,而在兴奋相关领域和自主神经领域则有微弱至中等程度的效应:中枢神经系统活性化合物 MK-801 的 Irwin 数据集存在明显的实验室间差异,在药物开发过程中做出决策时需要仔细考虑。虽然环境和一般研究设计的影响较小,但该研究表明,统一参数及其评分可以限制变异性并提高稳健性。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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