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OtherArticle

Predicting Volume of Distribution in Humans: Performance of in silico Methods for A Large Set of Structurally Diverse Clinical Compounds

Neha Murad, Kishore K. Pasikanti, Benjamin D. Madej, Amanda Minnich, Juliet M. McComas, Sabrinia Crouch, Joseph W. Polli and Andrew D. Weber
Drug Metabolism and Disposition November 25, 2020, DMD-AR-2020-000202; DOI: https://doi.org/10.1124/dmd.120.000202
Neha Murad
1GlaxoSmithKline, United States of America
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Kishore K. Pasikanti
2DMPK, GlaxoSmithKline, United States of America
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  • ORCID record for Kishore K. Pasikanti
  • For correspondence: kishore.k.pasikanti@gsk.com
Benjamin D. Madej
3Frederick National Laboratory for Cancer Research, United States of America
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Amanda Minnich
4Lawrence Livermore National Laboratory, United States of America
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Juliet M. McComas
1GlaxoSmithKline, United States of America
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Sabrinia Crouch
1GlaxoSmithKline, United States of America
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Joseph W. Polli
1GlaxoSmithKline, United States of America
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Andrew D. Weber
1GlaxoSmithKline, United States of America
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Data Supplement

  • Supplemental Data -

    Supplemental Table S1 - Machine learning (ML) models used to predict input parameters for various in silico VD,ss prediction methodologies 

    Supplemental Table S2 - Experimental measurement of physicochemical properties and observed VD,ss values (Lombardo et al., 2018) for 254 compounds

    Supplemental Table S3 - Experimental determination of adipocyte and myocyte cell partitioning of 189 clinical compounds (Lombardo et al., 2018).

    Supplemental Figure S1 - UMAP projection of datasets (a) ATOM in silico and (b)experimental set based on ECFP Tanimoto distances. 

    Supplemental Figure S2 - Scatter/KDE plots of observed versus predicted using various silico VD,ss prediction methodologies listed in Table 2 (a) ATOM in silico set (>940 compounds) and (b) ATOM experimental set (n>280 compounds). Crosslines indicate 2, 3 and 10-fold limits. 

    Supplemental Figure S3 - Measured ChromLogD compared to predicted LogD values by (a) ADMET Predictor (b) ATOM ML model. 

    Supplemental Figure S4 - Scatter/KDE plots of mechanistic VD,ss predictions using various combinations of experimental data (fup, BPR and LogD) as input parameters. 

    Supplemental Figure S5 - Scatter/KDE plots of mechanistic VD,ss predictions using various combinations of experimental data (Kp fat and Kp muscle) as input parameters. 

    Supplemental Figure S6 - Scatter plot of mechanistic VD,ss predictions color coded by ionization using various combinations of experimental data (fup, BPR and LogD) as input parameters.

    Supplemental Figure S7 - Scatter plots of predicted in silico vs observed VD,ss using (a) Allometry (Rat and Dog) and (b) ADMET Mechanistic models. Crosslines indicate 2, 3 and 10-fold limits.

  View article

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