Application of a variable direction hysteresis minimization approach in describing the central nervous system pharmacodynamic effects of alfentanil in rabbits.

The relationship between the concentration of a drug and its pharmacologic effect is of central interest in pharmacodynamics. Various compartmental and noncompartmental methods have been proposed for elucidating this relationship when the plasma drug concentration and effects are both measured. Although the relationship between drug input and the pharmacologic effect is equally useful, it has not received as much attention. A system analysis hysteresis minimization pharmacodynamic method was developed to describe the central nervous system effects of alfentanil in rabbits. The spectral edge frequency (SEF) was used as the effect measure and the infusion rate as the pharmacokinetic variable. The sigmoid Emax and cubic polynomial representations of the transduction relationship were investigated in modeling the collapsed hysteresis loop. The results indicated that alfentanil has a relatively rapid biophase equilibration time (t50 = 6 min). Both the sigmoid Emax and cubic polynomial transduction relationships were equally effective in describing the observed effect data and gave similar predictions. The proposed approach has the advantage of not assuming a specific compartmental structure for the pharmacokinetic-pharmacodynamic link. A particular advantage of the method is that no functional relationship is assumed a priori for the transduction relationship, and errors in both regression variables are considered in the optimization. The system analysis pharmacodynamic approach assumes linear disposition pharmacokinetics, an instantaneous and time-invariant transduction, and that inductive effects like tolerance or sensitization do not develop significantly in the time frame studied.