Variation of Cmax and Cmax/AUC in investigations of bioequivalence.

In order to enable the setting of regulatory criteria for the equivalence of absorption rates on a sound scientific basis, the variation of Cmax/AUC and Cmax was evaluated. Under most conditions, the variation of Cmax/AUC was 10-25% higher than that of AUC independently of the variability of the extent of absorption. By contrast, the variation of Cmax was 50-60% higher than that of AUC and was strongly dependent on the variability of the extent of absorption. Therefore, it is recommended that for establishing the equivalence of absorption rates, the 90% confidence limits for the percentage ratio of the Cmax/AUC values of two drug products should be (based on their logarithmic averages or medians) between 75 and 133%. Regulatory decisions based on Cmax, while not favored, should expect that the 90% confidence limits for the percentage ratio of the Cmax values of two drug products be (based on their logarithmic averages or medians) between 70 and 143%. These recommendations parallel and are contingent upon the internationally harmonized criterion for the equivalence of extents of absorption which requires that the 90% confidence limits for the percentage ratio of two AUC values (based on their logarithmic averages or medians) be between 80 and 125%.