Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena

A precursor-dependent model of indirect pharmacodynamic response which can describe tolerance and rebound was characterized in terms of the effects of changes in the fundamental properties of the drug on its response profiles. The model extends previous models by considering inhibition or stimulation of production of the response variable dependent on the amount of precursor which may accumulate or deplete after administration of some drugs. Standardized pharmacokinetic and pharmacodynamic parameters were used for generating dose, plasma concentration, and response-time profiles using computer simulations. The peak response (Rmax) and the time of its occurrence (TRmax) were dependent on the dose, degree of maximum inhibition (Imax) or stimulation (Smax), and drug concentrations causing 50% inhibition (IC50) or stimulation (SC50). The maximum rebound (RBmax) and the time of its occurrence (TRBmax) after a single bolus dose were also dependent on these factors, but were of lesser magnitude and showed relatively later occurrence. Interestingly, values of area between the baseline and effect curve (ABEC) and area between the baseline and rebound curve (ABRC) were equal for each set of conditions for each model, but the latter is reduced when there is a second pathway for loss of precursor. Tolerance occurs because of diverse mechanisms, and the response patterns demonstrated may be helpful in describing tolerance and rebound phenomena for drugs which affect precursor pools.