Mathematical formalism and characteristics of four basic models of indirect pharmacodynamic responses for drug infusions.

Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout) of the response variable. Partially integrated solutions for these models developed previously for i.v. bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and Kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of i.v. bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.