Pharmacodynamics hysteresis

C(t) modeled according to two-compartment model with zero-order and first-order absorption Pharmacokinetic/pharmacodynamic relationship modeled using Hill model with first-order absorption. Modeled parameters matched experimental parameters when bicompartmental model with zero-order input was used. Linear PKs, anticlockwise hysteresis loop established for all doses studied. Apomorphine and growth hormone concentration predicted with good accuracy... 

Under the assumptions of the direct-link model, neither a counterclockwise (Figure 10.2) nor a clockwise hysteresis loop (Figure 10.4) will be recorded in an effect vs. concentration plot. In principle, the shape of the effect vs. concentration plot for an ideal direct-link model will be a curve identical to the specific pharmacodynamic model, relating effect with concentration, e.g., linear for a linear pharmacodynamic model, sigmoid for the sigmoid Emax model (cf. Table 10.1 and following paragraphs and sections), etc. 

Figure 5.5 The relationship between pharmacodynamic effects and plasma drug concentrations showing anticlockwise hysteresis and the derived concentration-effect relationship at the effect site.

Counterclockwise hysteresis loops can be caused by the accumulation of an active metabolite, sensitization to the drug, or delay in time in equilibration between serum concentration and concentration of drug at the site of action. Combined pharmacokinetic-pharmacodynamic models have been devised that allow equilibration lag times to be taken into account. 

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