SENSITIVITY OF INDIRECT METRICS FOR ASSESSING RATE IN BIOEQUIVALENCE STUDIES - MOVING THE GOALPOSTS OR CHANGING THE GAME

The requirement to assess ''rate'' in bioequivalence tests using indir ect metrics reinforces ambiguities as to whether such testing is inten ded to assure both pharmaceutical quality with respect to drug release characteristics as well as clinical safety and efficacy. Using a one- compartment open pharmacokinetic model with first-order absorption and error-free data, the effects of systematically changing the ratio of the absorption rate constants of test and reference formulations on va rious indirect metrics of rate of drug absorption [maximum plasma conc entration (C-max), time to reach C-max(t(max)), mean residence time (M RT), partial area under the plasma concentration-time curve (AUC(t))] were evaluated as a function of the ratio of absorption rate constant to elimination rate constant. This simple simulation illustrates the p itfall of judging the performance of different indirect rate metrics o n the basis of a fixed universal acceptance interval for bioequivalenc e. However, turning the issue on its head, since rate, as indicated by a rate constant, cannot be assessed accurately using indirect metrics and may have little clinical relevance, regulatory guidelines should emphasize the use of C-max and other measures taken from the plasma dr ug concentration-time curve as empirical indices of safety and efficac y. The acceptance limits should then depend on clinical criteria and t he variability of the reference formulation.