The Use of Multiple Doses and Pharmacodynamic System Analysis to Distinguish Between Dispositional Delays and Time-Variant Pharmacodynamics
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Pharmacokinetic-pharmacodynamic modeling algorithms, in general, rely on hysteresis minimization techniques that assume time-invariant pharmacodynamics (constant biophase concentration-effect relationships). When time-variant pharmacodynamics are observed, a specific model for tolerance or sensitization is required. However, with single dosing, hysteresis that results from a time-variant biophase concentration-effect relationship cannot be distinguished from hysteresis caused by dispositional delays. This can lead to the inappropriate minimization of hysteresis. As an approach to this problem, simulated and real kinetic-dynamic data were analyzed with the pharmacodynamic system analysis program ATTRACT. The use of a multiple dosing regimen and this hysteresis minimization algorithm resulted in a simple diagnostic test to distinguish between dispositional effects of acute tolerance and sensitization.
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