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Time dependent analysis of assay comparability: a novel approach to understand intra- and inter-site variability over time

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Abstract

We demonstrate here a novel use of statistical tools to study intra- and inter-site assay variability of five early drug metabolism and pharmacokinetics in vitro assays over time. Firstly, a tool for process control is presented. It shows the overall assay variability but allows also the following of changes due to assay adjustments and can additionally highlight other, potentially unexpected variations. Secondly, we define the minimum discriminatory difference/ratio to support projects to understand how experimental values measured at different sites at a given time can be compared. Such discriminatory values are calculated for 3 month periods and followed over time for each assay. Again assay modifications, especially assay harmonization efforts, can be noted. Both the process control tool and the variability estimates are based on the results of control compounds tested every time an assay is run. Variability estimates for a limited set of project compounds were computed as well and found to be comparable. This analysis reinforces the need to consider assay variability in decision making, compound ranking and in silico modeling.

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Acknowledgments

We want to acknowledge the Wave1 assay teams at Alderley Park, Mölndal, Boston and our external partner for their work to run the assays and thereby provide the values we used for this analysis.

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Authors and Affiliations

  1. Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden

    Susanne Winiwarter & Claire Landqvist

  2. Innovative Medicines, Discovery Sciences, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK

    Brian Middleton

  3. Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Cambridge, Unit 310 - Darwin Building, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK

    Barry Jones

  4. Global Medicines Development, Pharmaceutical Development, AstraZeneca R&D, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK

    Paul Courtney

  5. Innovative Medicines, Cardiovascular and Metabolic Diseases, AstraZeneca R&D Mölndal, Pepparedsleden 1, 43183, Mölndal, Sweden

    Bo Lindmark

  6. Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK

    Ken M. Page

  7. Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Boston, 35 Gatehouse Park, Waltham, MA, 01742, USA

    Alan Clark

Authors
  1. Susanne Winiwarter
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  2. Brian Middleton
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  3. Barry Jones
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  4. Paul Courtney
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  5. Bo Lindmark
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  6. Ken M. Page
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  7. Alan Clark
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  8. Claire Landqvist
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Correspondence to Susanne Winiwarter.

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Winiwarter, S., Middleton, B., Jones, B. et al. Time dependent analysis of assay comparability: a novel approach to understand intra- and inter-site variability over time. J Comput Aided Mol Des 29, 795–807 (2015). https://doi.org/10.1007/s10822-015-9836-5

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  • DOI: https://doi.org/10.1007/s10822-015-9836-5

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