Bioequivalence and Bioavailability Forum

❝ VICH GL52 mentions evaluation of AUC0-LOQ insterad of the AUC0-t we have in human studies? Would AUC0-LOQ be the same as AUC0-t?

❝ The guideline doesnt cover NTI and HVD.

For AUC, the ratio of the two treatment means should be entirely contained within the limits 80% to 125%. The acceptance limits for C_max and C_min should also generally be within 80% to 125%. However, as these parameters may exhibit a greater intra-indi­vi­dual variability, a maximal widening of the limits to 70% to 143% could in rare cases be acceptable if it has been pro­spec­tively defined in the protocol together with a justi­fi­ca­tion from efficacy and safety perspectives.

For substances with highly variable disposition where it is difficult to show bio­equi­va­lence due to high intra individual variability, different alternative designs have been suggested in literature. It is recommended to ask for scientific advice if it is estimated that a traditional crossover design would not be feasible without the inclusion of a very high number of animals.

Although it is likely that this approach would be accepted in practice we prefer not to detail this in the guideline. This is one of several approaches to handle highly variable drugs.