Exploratory and Population Pharmacodynamic Analysis of Pilot Dose-Response Data in the Bioequivalence Testing of Topical Corticosteroid Preparations

Abstract

A guidance of the Food and Drug Administration (FDA) recommends that the pharmacodynamic (PD) equivalence of topical corticosteroid preparations be demonstrated by a two-step procedure. A pilot study would establish the ED50 of a PD relationship between dose duration and a vasoconstrictor response. The relevance of the assumed hyperbolic Michaelis-Menten response model is evaluated by both graphical exploratory and population PD analyses of the data presented in the guidance. It is shown that the observations are far removed from their asymptotic plateau, and that they can be characterized well by a simplified Hill equation with a Hill coefficient of 0.4. Consequently, it is suggested that pilot studies are not needed when the dose range for sensitive responses is known. Nonresponding subjects should be removed from the analyses of both stages of an investigation. PD equivalence should be assessed with dose durations distanced as far as possible from each other. Finally, the study demonstrates the usefulness of graphical, exploratory analyses without which modeling by regression, including population kinetic and PD computations, can be misinterpreted.