Limits of 80% – 125% for AUC and 70% – 143% for Cmax. What is the impact on bioequivalence studies?

OBJECTIVE: The US Food and Drug Administration (FDA) currently uses bioequivalence (BE) limits for fasting BE studies that are based on the 90% confidence interval for the ratio of difference of the test and reference products Cmax and AUC falling within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and Cmax measurements from fed BE studies. In some cases, regulatory agencies have considered a wider BE limit for Cmax, because of the typically higher variability of Cmax compared to AUC. 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 Cmax. METHODS: We computed the sample sizes required for BE studies using 80%/125% for AUC and 70%/143% for Cmax as BE limits. We also determined the range of the ratios of Cmax and AUC values in a study that 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 70%/143% for Cmax, will be determined primarily by the intrasubject variability of AUC, though with a substantial proportion of studies (about one third) still determined by the variability of Cmax. The ratio of mean Cmax values 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 Cmax to 70%/143% for either fasting or fed BE studies.