The Use of ROC Analysis for the Qualitative Prediction of Human Oral Bioavailability from Animal Data

Andrés Olivares-Morales, Oliver J D Hatley, David Turner, Aleksandra Galetin, Leon Aarons, Amin Rostami-Hodjegan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Purpose: To develop and evaluate a tool for the qualitative prediction of human oral bioavailability (Fhuman) from animal oral bioavailability (Fanimal) data employing ROC analysis and to identify the optimal thresholds for such predictions. Methods: A dataset of 184 compounds with known Fhuman and Fanimal in at least one species (mouse, rat, dog and non-human primates (NHP)) was employed. A binary classification model for Fhuman was built by setting a threshold for high/low F human at 50%. The thresholds for high/low Fanimal were varied from 0 to 100 to generate the ROC curves. Optimal thresholds were derived from 'cost analysis' and the outcomes with respect to false negative and false positive predictions were analyzed against the BDDCS class distributions. Results: We successfully built ROC curves for the combined dataset and per individual species. Optimal Fanimal thresholds were found to be 67% (mouse), 22% (rat), 58% (dog), 35% (NHP) and 47% (combined dataset). No significant trends were observed when sub-categorizing the outcomes by the BDDCS. Conclusions: Fanimal can predict high/low Fhuman with adequate sensitivity and specificity. This methodology and associated thresholds can be employed as part of decisions related to planning necessary studies during development of new drug candidates and lead selection. © 2013 Springer Science+Business Media New York.
    Original languageEnglish
    Pages (from-to)720-730
    Number of pages10
    JournalPharmaceutical Research
    Volume31
    Issue number3
    DOIs
    Publication statusPublished - 27 Sep 2013

    Keywords

    • BDDCS
    • interspecies
    • oral bioavailability
    • qualitative prediction
    • ROC analysis

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