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A High-throughput Assay for the Prediction of Chemical Toxicity by Automated Phenotypic Profiling of Caenorhabditis elegans
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A High-throughput Assay for the Prediction of Chemical Toxicity by Automated Phenotypic Profiling of Caenorhabditis elegans

Published on: March 14, 2019

Quantitative prediction of drug toxicity in humans from toxicology in small and large animals

M A Goldsmith, M Slavik, S K Carter

    Cancer Research
    |May 1, 1975
    PubMed

    Insights

    Predicting human toxicity from animal data is crucial for safe drug development. Mouse toxicity data, particularly lethal doses and optimal tumor doses, offers a reliable method for determining safe starting doses in early-phase clinical trials.

    Area of Science:

    • Pharmacology
    • Toxicology
    • Preclinical Research

    Background:

    • Accurate prediction of human toxicity from animal models is essential for safe clinical drug development.
    • Current methods for selecting starting doses in Phase 1 clinical trials may not sufficiently account for interspecies variability.
    • Retrospective analysis of existing toxicity data can refine predictive models for human drug response.

    Purpose of the Study:

    • To retrospectively analyze mouse, dog, and monkey toxicity data for 30 drugs against human clinical dose schedules.
    • To evaluate the predictive value of various animal toxicity metrics for human toxicity.
    • To determine optimal strategies for selecting safe and effective starting doses for Phase 1 clinical trials.

    Main Methods:

    • Retrospective analysis of toxicity data from mouse, dog, and monkey studies for 30 drugs.
    • Conversion of animal dose schedules to human-equivalent doses (mg/sq m).
    • Comparison of human doses with animal toxic doses (low, high, lethal) and mouse lethal doses (LD10, LD90) and optimal tumor doses.

    Main Results:

    • Using one-third of the toxic low dose in the most sensitive large animal species could have led to significant toxicity in 5 out of 30 drugs in Phase 1 trials.
    • Lethal doses for 10% and 90% of normal mice (LD10, LD90) and the optimal dose in L1210-bearing mice provided good quantitative prediction of human toxicity.
    • Toxicology data from both normal and tumor-bearing mice, alongside dog and monkey data, is vital for safe starting dose determination.

    Conclusions:

    • Mouse toxicity data, including lethal doses and optimal tumor doses, are valuable predictors of human toxicity.
    • Relying solely on large animal data (dog, monkey) may underestimate toxicity risks for certain drugs.
    • A comprehensive approach incorporating diverse animal toxicology data is necessary for establishing safe and practical Phase 1 starting doses.

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