The maximum pharmacodynamic effect as a response parameter: Pharmacokinetic considerations

In previous human in-vivo studies measuring the maximum pharmacodynamic response to characterize cutaneously applied ointment preparations, it was observed that differences between various formulations caused by penetration enhancement led to different enhancement factors depending on the method used for determination of these factors from activity-reponse curves. To clarify this discrepancy, pharmacokinetic simulations have been performed based on an open one-compartment model with either first- or zero-order drug penetration kinetics and first-order elimination kinetics. Under the assumption that the maximum pharmacodynamic response corresponds to the maximum effective drug concentration in the receptor compartment, which represents the difference between the maximum drug concentration and the threshold concentration, drug concentration vs time profiles and dose-reponse curves were simulated. In addition, maximum effective concentrations were calculated and plotted against the logarithm of the thermodynamic drug activity to obtain activity-reponse curves. Relative bioavailability and enhancement factors were determined either from the horizontal distance between the curves of a standard and a test preparation, or as the ratio of the maximum effective concentration of test and standard formulations. A significant difference between the first-order and the zero-order input kinetics with regard to the evaluation of bioavailability and drug penetration enhancement was shown. Under finite dose conditions, i.e. first-order input kinetics from solution-type preparations, a misestimation of the factors usually occurs. Only under infinite dose conditions, i.e. if large preparation volumes are applied to achieve zero-order input kinetics, is the determination of bioavailability and enhancement factors from dose- and activity-reponse curves accurate.