title: Time dependent analysis of assay comparability: a novel approach to understand intra- and inter-site variability over time.
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.
authors.affiliation: Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden. susanne.winiwarter@astrazeneca.com.
authors.forename: Susanne
authors.initials: S
authors.lastname: Winiwarter
authors.affiliation: Innovative Medicines, Discovery Sciences, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Middleton
authors.affiliation: Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Cambridge, Unit 310 - Darwin Building, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Jones
authors.affiliation: Global Medicines Development, Pharmaceutical Development, AstraZeneca R&D, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Courtney
authors.affiliation: Innovative Medicines, Cardiovascular and Metabolic Diseases, AstraZeneca R&D Mölndal, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Lindmark
authors.affiliation: Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Ken M
authors.initials: KM
authors.lastname: Page
authors.affiliation: Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Boston, 35 Gatehouse Park, Waltham, MA, 01742, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Clark
authors.affiliation: Innovative Medicines, Drug Safety and Metabolism, AstraZeneca R&D Mölndal, Pepparedsleden 1, 431 83, Mölndal, Sweden.
authors.forename: Claire
authors.initials: C
authors.lastname: Landqvist
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000706:statistics & numerical data; D001798:Blood Proteins / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods* / Q000706:statistics & numerical data*; D006801:Humans; D008658:Inactivation, Metabolic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010599:Pharmacokinetics; D051381:Rats; D012995:Solubility
chemical_list: D001798:Blood Proteins; D004364:Pharmaceutical Preparations
keywords: ADME; DMPK; Screening assay; Site variability; Variability