Metrics for the evaluation of bioequivalence of modified-release formulations.

Metrics are discussed which are used for the evaluation of bioequivalence of modified-release formulations. In order to ensure the therapeutic equivalence of the compared drug products, it would be important to contrast measures which are additional to area under the curve (AUC) and C (max). For delayed-release products, the assessment of lag times is informative. For extended-release dosage forms, comparisons of the half-value duration and the midpoint duration time are useful. For some modified-release formulations with complicated, multiphasic concentration profiles, the comparison of partial AUCs is important. In determinations of the bioequivalence of extended-release dosage forms, investigations performed under steady-state conditions rather than after single dosing can yield enhanced probability of therapeutic equivalence, especially with substantial accumulation of the drug products. In steady-state investigations of bioequivalence, evaluation of the trough concentration and of the peak trough fluctuation is informative

The Two Main Goals of Bioequivalence Studies.

The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits. Both points of view are valid since they represent two aspects of product performance. It has been argued that both should be equally sustained and applied. In practice, however, they collide when regulatory conditions and statements are developed. For instance, some regulators prefer to conduct BE studies following single drug administrations since these conditions are considered to provide the highest sensitivity of discrimination between pharmacokinetic profiles and thus, a product's in-vivo performance. Others suggest that, at least for modified-release products, BE investigations should be performed in the steady state since it represents clinical conditions. Preference for one point of view or the other pervades other regulatory statements including suggestions for subjects to be selected in studies and pharmacokinetic measures to be evaluated. An overview is provided on the disturbing inconsistency of statements within and between regulations. It is argued that harmonization would be highly desirable, and relevant recommendations are offered