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A system approach to pharmacodynamics. III: An algorithm and computer program, COLAPS, for pharmacodynamic modeling.

P Veng-Pedersen1, J W Mandema, M Danhof

  • 1University of Iowa, College of Pharmacy, Iowa City 52242.

Journal of Pharmaceutical Sciences
|May 1, 1991
PubMed
Summary

A new model-independent algorithm, COLAPS, empirically determines pharmacodynamic (PD) model components N and L without assuming specific kinetic structures. This approach offers greater generality than traditional methods and successfully analyzed amobarbital PD, revealing biphasic behavior.

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Area of Science:

  • Pharmacodynamics
  • Systems Biology
  • Computational Pharmacology

Background:

  • Pharmacodynamic (PD) models describe drug effects but often rely on specific kinetic structures.
  • Existing models, like effect compartment models, have limitations in generality.
  • A generalized model form E(t) = N(L[c(t)]) encompasses a broader class of PD relationships.

Purpose of the Study:

  • To present a model-independent algorithm, COLAPS, for empirically determining components of generalized PD models.
  • To introduce a method that avoids assumptions about specific kinetic structures.
  • To analyze the PD of amobarbital using the developed algorithm.

Main Methods:

  • Developed the COLAPS algorithm based on system analysis and hysteresis minimization.

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  • Employed concepts of biophase conduction and transduction functions.
  • Utilized a transformation technique and novel reparameterization for enhanced flexibility and to prevent improper convergence.
  • Applied inequality function constraints without constrained nonlinear optimization.

    • Main Results:

    • COLAPS successfully minimized hysteresis between drug effect and biophase drug levels.
    • The algorithm determined the biophase conduction function, normalized biophase drug level, and transduction curve.
    • The determined transduction curve exhibited clear biphasic behavior, indicating complex drug response dynamics.

    Conclusions:

    • The COLAPS algorithm provides a general and flexible approach to PD modeling, independent of specific kinetic assumptions.
    • This method overcomes limitations of traditional models and offers a robust way to analyze drug effects.
    • The analysis of amobarbital demonstrates the practical utility of COLAPS in uncovering complex kinetic-dynamic relationships.