Sensitivity of indirect metrics for assessing "rate" in bioequivalence studies--moving the "goalposts" or changing...

The requirement to assess "rate" in bioequivalence tests using indirect metrics reinforces ambiguities as to whether such testing is intended 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 various indirect metrics of rate of drug absorption [maximum plasma concentration (Cmax), time to reach Cmax (tmax), mean residence time (MRT), 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 pitfall of judging the performance of different indirect rate metrics on the basis of a fixed universal acceptance interval for bioequivalence. 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 Cmax and other measures taken from the plasma drug concentration-time curve as empirical indices of safety and efficacy. The acceptance limits should then depend on clinical criteria and the variability of the reference formulation.