The use of multiple doses and pharmacodynamic system analysis to distinguish between dispositional delays and time-variant pharmacodynamics.
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.
Gastonguay
M R
MR
Department of Pharmacology, Georgetown University School of Medicine, Washington, D.C. 20007.
Schwartz
S L
SL
D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics