Bioequivalence and Bioavailability Forum

Hi John,

❝ Has anyone seen a BE study failing due to AUCinf falling outside 80-125% and the variability in the results seem to be attributed to the determination of Kel (jumpy concentrations)?

From a European perspective, AUC_∞ doesn’t bother me (BE only required for AUC_t). Sometimes sponsors wanted me to assess BE of AUC_∞ as ‘supportive information’ (for some wacky reasons I don’t understand). As expected regularly the CV was higher. Wouldn’t surprise me if there are studies in the wild passing AUC_t and failing AUC_∞. Kamal Midha gave numerous presentations showing dependency of the variability of partial AUCs from the truncation time point. The CV is (sometimes prohibitively) large during the – early absorption phase and decreases afterwards. Sometimes the variability slightly increases again during the latest time points since the variability of concentrations approaching the LLOQ increases. AUC_∞ was generally more variable than AUC_t.
Funny enough it was shown already two decades ago that AUC_∞ is a bad metric for extent of absorption.* Some of the authors were usual suspects from the FDA. From the abstract:

The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and C_max.

(my emphasis)
Lessons not learned.

❝ Sampling timepoint setup was adequate in terms of capturing the terminal eleminaition phase of the PK profile. I wonder if there is any way to save this study.

Duno. Maybe you can start an argument that AUC_∞ is not a reliable PK metric. According to the paper AUC_∞ is not only more variable, but may also be biased (depending on the PK model and the LLOQ). On the other hand both AUCs are required. Good luck.

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• Bois FY, Tozer TN, Hauck WW, Chen M-L, Patnaik R, Williams RL. Bioequivalence: Performance of Several Measures of Extent of Absorption. Pharm Res. 1994;11(5):715–22. doi:10.1023/A:1018932430733.