A systematic assessment of robustness in CNS safety pharmacology.
adverse drug reaction
mouse
multicentre
multilaboratory
reproducibility
research design
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
10 Oct 2024
10 Oct 2024
Historique:
revised:
04
06
2024
received:
01
03
2024
accepted:
26
08
2024
medline:
11
10
2024
pubmed:
11
10
2024
entrez:
10
10
2024
Statut:
aheadofprint
Résumé
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. Female and male NMRI mice were assigned to one of three groups (vehicle, MK-801 0.1 and 0.3 mg kg 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. 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.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
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
METHODS
Female and male NMRI mice were assigned to one of three groups (vehicle, MK-801 0.1 and 0.3 mg kg
KEY RESULTS
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
CONCLUSIONS
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Innovative Medicines Initiative 2 Joint Undertaking
ID : 777364
Organisme : German Research Foundation
ID : BL953/11-1
Organisme : German Research Foundation
ID : BL953/11-2
Informations de copyright
© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Alexander, S. P. H., Mathie, A. A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Aldrich, R. W., Attali, B., Baggetta, A. M., Becirovic, E., Biel, M., Bill, R. M., Caceres, A. I., Catterall, W. A., Conner, A. C., … Zhu, M. (2023). The concise guide to PHARMACOLOGY 2023/24: Ion channels. British Journal of Pharmacology, 180(Suppl 2), S145–S222. https://doi.org/10.1111/bph.16178
Arroyo‐Araujo, M., Voelkl, B., Laloux, C., Novak, J., Koopmans, B., Waldron, A. M., Seiffert, I., Stirling, H., Aulehner, K., Janhunen, S. K., Ramboz, S., Potschka, H., Holappa, J., Fine, T., Loos, M., Boulanger, B., Würbel, H., & Kas, M. J. (2022). Systematic assessment of the replicability and generalizability of preclinical findings: Impact of protocol harmonization across laboratory sites. PLoS Biology, 20(11), e3001886. https://doi.org/10.1371/journal.pbio.3001886
Bespalov, A., Bernard, R., Gilis, A., Gerlach, B., Guillén, J., Castagné, V., Lefevre, I. A., Ducrey, F., Monk, L., Bongiovanni, S., Altevogt, B., Arroyo‐Araujo, M., Bikovski, L., de Bruin, N., Castaños‐Vélez, E., Dityatev, A., Emmerich, C. H., Fares, R., Ferland‐Beckham, C., … Steckler, T. (2021). Introduction to the EQIPD quality system. eLife, 10, e63294. https://doi.org/10.7554/eLife.63294
Crofton, K. M., Howard, J. L., Moser, V. C., Gill, M. W., Reiter, L. W., Tilson, H. A., & MacPhail, R. C. (1991). Interlaboratory comparison of motor activity experiments: Implications for neurotoxicological assessments. Neurotoxicology and Teratology, 13(6), 599–609. https://doi.org/10.1016/0892-0362(91)90043-V
Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. British Journal of Pharmacology, 179, 3907–3913. https://doi.org/10.1111/bph.15868
Errington, T. M., Mathur, M., Soderberg, C. K., Denis, A., Perfito, N., Iorns, E., & Nosek, B. A. (2021). Investigating the replicability of preclinical cancer biology. eLife, 10, e71601. https://doi.org/10.7554/eLife.71601
European Medicines Agency. (2001). Note for guidance on safety pharmacology studies for human pharmaceuticals (CPMP/ICH/539/00). Retrieved 10/19/23 from: https://www.ema.europa.eu/en/ich-s7a-safety-pharmacology-studies-human-pharmaceuticals
Gad, S. C., & Gad, S. E. (2003). A functional observational battery for use in canine toxicity studies: Development and validation. International Journal of Toxicology, 22(6), 415–422. https://doi.org/10.1177/109158180302200602
Gauvin, D. V., & Baird, T. J. (2008). A functional observational battery in non‐human primates for regulatory‐required neurobehavioral assessments. Journal of Pharmacological and Toxicological Methods, 58(2), 88–93. https://doi.org/10.1016/j.vascn.2008.05.002
Gauvin, D. V., & Zimmermann, Z. J. (2019). FOB vs modified Irwin: What are we doing? Journal of Pharmacological and Toxicological Methods, 97, 24–28. https://doi.org/10.1016/j.vascn.2019.02.008
Gauvin, D. V., Zimmermann, Z. J., Dalton, J. A., & Baird, T. J. (2017). Repeated “Day 1” FOB testing in ICH S7A safety assessment protocols: The influence of within‐ and between‐session learning. Journal of Pharmacological and Toxicological Methods, 85, 61–72. https://doi.org/10.1016/j.vascn.2017.02.018
Giles, J. (2006). Animal experiments under fire for poor design. Nature, 444(7122), 981. https://doi.org/10.1038/444981a
Gouveia, K., & Hurst, J. L. (2017). Optimising reliability of mouse performance in behavioural testing: The major role of non‐aversive handling. Scientific Reports, 7, 44999. https://doi.org/10.1038/srep44999
Himmel, H. M., Delaunois, A., Deurinck, M., Dinklo, T., Eriksson Faelker, T. M., Habermann, C., Heers, C., Hempel, K., Lorenz, H., Rosch, A., Schauerte, H., Teuns, G., Traebert, M., van Amsterdam, C., & van der Linde, H. (2019). Variability of non‐clinical behavioral CNS safety assessment: An intercompany comparison. Journal of Pharmacological and Toxicological Methods, 99, 106571. https://doi.org/10.1016/j.vascn.2019.03.002
Irwin, S. (1968). Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia, 13(3), 222–257. https://doi.org/10.1007/bf00401402
Jackson, S. J., Authier, S., Brohmann, H., Goody, S. M. G., Jones, D., Prior, H., Rosch, A., Traebert, M., Tse, K., Valentin, J. P., & Milne, A. (2019). Neurofunctional test batteries in safety pharmacology—Current and emerging considerations for the drug development process. Journal of Pharmacological and Toxicological Methods, 100, 106602. https://doi.org/10.1016/j.vascn.2019.106602
Kafkafi, N., Agassi, J., Chesler, E. J., Crabbe, J. C., Crusio, W. E., Eilam, D., Gerlai, R., Golani, I., Gomez‐Marin, A., Heller, R., Iraqi, F., Jaljuli, I., Karp, N. A., Morgan, H., Nicholson, G., Pfaff, D. W., Richter, S. H., Stark, P. B., Stiedl, O., … Benjamini, Y. (2018). Reproducibility and replicability of rodent phenotyping in preclinical studies. Neuroscience and Biobehavioral Reviews, 87, 218–232. https://doi.org/10.1016/j.neubiorev.2018.01.003
Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P. H., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of Pharmacology: Updated guidance for 2020. British Journal of Pharmacology, 177, 3611–3616. https://doi.org/10.1111/bph.15178
Loken, E., & Gelman, A. (2017). Measurement error and the replication crisis. Science, 355(6325), 584–585. https://doi.org/10.1126/science.aal3618
Löscher, W., & Fiedler, M. (1996). The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. VI. Seasonal influences on maximal electroshock and pentylenetetrazol seizure thresholds. Epilepsy Research, 25(1), 3–10. https://doi.org/10.1016/0920-1211(96)00022-8
Löscher, W., & Fiedler, M. (2000). The role of technical, biological, and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. VII. Seasonal influences on anticonvulsant drug actions in mouse models of generalized seizures. Epilepsy Research, 38(2–3), 231–248. https://doi.org/10.1016/s0920-1211(99)00095-9
Lynch, J. J. 3rd, Castagné, V., Moser, P. C., & Mittelstadt, S. W. (2011). Comparison of methods for the assessment of locomotor activity in rodent safety pharmacology studies. Journal of Pharmacological and Toxicological Methods, 64(1), 74–80. https://doi.org/10.1016/j.vascn.2011.03.003
Mathiasen, J. R., & Moser, V. C. (2018). The Irwin test and functional observational battery (FOB) for assessing the effects of compounds on behavior, physiology, and safety pharmacology in rodents. Current Protocols in Pharmacology, 83(1), e43. https://doi.org/10.1002/cpph.43
Mead, A. N., Amouzadeh, H. R., Chapman, K., Ewart, L., Giarola, A., Jackson, S. J., Jarvis, P., Jordaan, P., Redfern, W., Traebert, M., Valentin, J. P., & Vargas, H. M. (2016). Assessing the predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials. Regulatory Toxicology and Pharmacology, 80, 348–357. https://doi.org/10.1016/j.yrtph.2016.05.002
Moscardo, E., Maurin, A., Dorigatti, R., Champeroux, P., & Richard, S. (2007). An optimised methodology for the neurobehavioural assessment in rodents. Journal of Pharmacological and Toxicological Methods, 56(2), 239–255. https://doi.org/10.1016/j.vascn.2007.03.007
Moscardo, E., McPhie, G., Fasdelli, N., Giarola, A., Tontodonati, M., Dorigatti, R., & Meecham, K. (2010). An integrated cardiovascular and neurobehavioural functional assessment in the conscious telemetered cynomolgus monkey. Journal of Pharmacological and Toxicological Methods, 62(2), 95–106. https://doi.org/10.1016/j.vascn.2010.06.006
Moser, V. C. (1991). Applications of a neurobehavioral screening battery. Journal of the American College of Toxicology, 10(6), 661–669. https://doi.org/10.3109/10915819109078658
Moser, V. C., Becking, G. C., Cuomo, V., Frantík, E., Kulig, B. M., MacPhail, R. C., Tilson, H. A., Winneke, G., Brightwell, W. S., Cagiano, R., Gill, M. W., Haggerty, G. C., Hornychová, M., Lammers, J., Larsen, J. J., McDaniel, K. L., Nelson, B. K., & Ostergaard, G. (1997). The IPCS collaborative study on neurobehavioral screening methods: III. Results of proficiency studies. Steering group. Neurotoxicology, 18(4), 939–946.
Paylor, R. (2009). Questioning standardization in science. Nature Methods, 6(4), 253–254. https://doi.org/10.1038/nmeth0409-253
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., Garner, P., Holgate, S. T., Howells, D. W., Karp, N. A., Lazic, S. E., Lidster, K., MacCallum, C. J., Macleod, M., … Würbel, H. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biology, 18(7), e3000410. https://doi.org/10.1371/journal.pbio.3000410
Potschka, H. (2024). A systematic assessment of robustness in CNS safety pharmacology. Figshare. Dataset. https://doi.org/10.6084/m9.figshare.26947822.v1
Richter, S. H., Garner, J. P., & Würbel, H. (2009). Environmental standardization: Cure or cause of poor reproducibility in animal experiments? Nature Methods, 6(4), 257–261. https://doi.org/10.1038/nmeth.1312
Rogers, D. C., Fisher, E. M., Brown, S. D., Peters, J., Hunter, A. J., & Martin, J. E. (1997). Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mammalian Genome, 8(10), 711–713. https://doi.org/10.1007/s003359900551
Steckler, T., Macleod, M., Kas, M. J. H., Gilis, A., & Wever, K. E. (2018). European quality in preclinical data (EQIPD): Een breed consortium voor het verbeteren van de kwaliteit van proefdieronderzoek. Biotech, 57(2), 18–23.
Steward, O., & Balice‐Gordon, R. (2014). Rigor or mortis: Best practices for preclinical research in neuroscience. Neuron, 84(3), 572–581. https://doi.org/10.1016/j.neuron.2014.10.042
Tontodonati, M., Fasdelli, N., Moscardo, E., Giarola, A., & Dorigatti, R. (2007). A canine model used to simultaneously assess potential neurobehavioural and cardiovascular effects of candidate drugs. Journal of Pharmacological and Toxicological Methods, 56(2), 265–275. https://doi.org/10.1016/j.vascn.2007.03.005
Tse, K., Sillito, R., Keerie, A., Collier, R., Grant, C., Karp, N. A., Vickers, C., Chapman, K., Armstrong, J. D., & Redfern, W. S. (2018). Pharmacological validation of individual animal locomotion, temperature and behavioural analysis in group‐housed rats using a novel automated home cage analysis system: A comparison with the modified Irwin test. Journal of Pharmacological and Toxicological Methods, 94(Pt 1), 1–13. https://doi.org/10.1016/j.vascn.2018.03.008
Usui, T., Macleod, M. R., McCann, S. K., Senior, A. M., & Nakagawa, S. (2021). Meta‐analysis of variation suggests that embracing variability improves both replicability and generalizability in preclinical research. PLoS Biology, 19(5), e3001009. https://doi.org/10.1371/journal.pbio.3001009
Zhong, M., Shoemake, C., Fuller, A., White, D., Hanks, C., Brocksmith, D., Liu, J., Gad, S., Bouchard, G., & Stricker‐Krongrad, A. (2017). Development of a functional observational battery in the Minipig for regulatory neurotoxicity assessments. International Journal of Toxicology, 36(2), 113–123. https://doi.org/10.1177/1091581816686049