Bioequivalence and Bioavailability Forum

Dear Helmut & Sam,
Thanks a lot!

❝ Good question, next question. Note that “t” is defined as the time point of the last quantifiable concentration. Your primary metric is not AUC₃₆. But it’s true that missing values / <LLOQ will also lead to “apples-and-oranges” (old story). BTW, have you ever seen in a steady-state study Phoenix/WinNonlin reporting AUClast ≠ AUCtau? If yes, can you guess why?

Is it because AUClast considers area up to last quantifiable concentration and AUCtau only considers area between dosing interval?

I am still confused about comparing AUC8hrs of one subject with AUC 36hrs of other subject, what is your suggestion on it?

In fact I would like to add a situation I have faced in couple of studies for pMDI formulation (with and without charcoal treatment), for Salmeterol I got AUC% extrapolation more than 20 % in about 35 % of the population and most of the subjects achieved either zero concentration much before the last concentration or had very slight concentration at last time point, actually a straight line was seen in the elimination phase because of which although samples were collected sufficient time period (up to 18 hrs post dose), AUC% extrapolation was greater than 20%. Following is a profile typically seen in most of the subjects but we got a query from regulator over it for validity of the as per guideline?



Can we have some justification for such issue?


Best Regards,

Ratnakar