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Related Experiment Videos

Quantitative analysis of the disopyramide concentration-effect relationship

B Whiting, N H Holford, L B Sheiner

    British Journal of Clinical Pharmacology
    |January 1, 1980
    PubMed
    Summary

    Disopyramide administration, whether intravenous or oral, causes QT prolongation. This study developed a model to link drug concentration to this effect, finding a consistent relationship regardless of administration route.

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    Area of Science:

    • Pharmacology
    • Clinical Pharmacology
    • Biomathematics

    Background:

    • Understanding the relationship between drug concentration and its effects is crucial for safe and effective drug use.
    • Disopyramide is an antiarrhythmic drug known to affect cardiac repolarization.

    Purpose of the Study:

    • To analyze the relationship between disopyramide plasma concentration and QT interval prolongation.
    • To develop and validate a combined pharmacokinetic-pharmacodynamic (PK/PD) model for disopyramide.

    Main Methods:

    • Utilized a combined PK/PD model incorporating an 'effect compartment' to analyze data from eight healthy subjects.
    • Administered disopyramide intravenously and orally.
    • Adjusted the model for the lag time between plasma concentration changes and observed effect.

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    Main Results:

    • A consistent relationship was observed between disopyramide plasma concentration and QT prolongation, irrespective of administration route (IV or oral).
    • The mean QT prolongation was 14.5 +/- 6.5 ms per microgram/mL.
    • No significant contribution of metabolites from first-pass metabolism to the observed effect was detected.

    Conclusions:

    • The developed PK/PD modeling technique effectively links disopyramide concentration to QT prolongation.
    • This modeling approach is potentially applicable to studying concentration-effect relationships for other drugs in various health conditions.