Limits of 80%-125% for AUC and 70%-143% for C-max - What is the impact on bioequivalence studies?

Objective: The US Food and Drug Administration (FDA) currently uses bioequi valence (BE) limits for fasting BE studies that are based on the 90% confid ence interval for the ratio of difference of the test and reference product s C-max and AUC failing within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and Cma, measurements from fed BE studi es. In some cases, regulatory agencies have considered a wider BE limit for C-max, because of the typically higher variability of C-max compared to AU C. We investigated the consequences of changing from an 80%/125% limit for both pharmacokinetic measures to one that uses a limit of 80%/125% for AUC and 70%/143% for C-max. Methods: We computed the sample sizes required for BE studies using 80%/125% for AUC and 70%/143% for C-max as BE limits. We a lso determined the range of the ratios Of Cmax and AUC values in a study th at could meet the 70%/143% and 80%/125% BE limits. Results: The sample size for the study, in order to have adequate power with 80%/125% for AUC and 7 0%/143% for C-max will be determined primarily by the intrasubject variabil ity of AUC, though with a substantial proportion of studies (about one thir d) still determined by the variability Of C-max The ratio of mean C-max val ues that can pass a wider 70%/143% BE limit could easily be as high as 128% . Conclusion: Without further scientific or clinical rationale, we find it difficult to justify widening the bioequivalence limit for C-max to 70%/143 % for either fasting or fed BE studies.