## Carrot and whip [Regulatives / Guidelines]

Dear Helmut! I'm grateful for your reply!

» Read the entire thread again.

Ok, my HW was not perfect No I reread it. Still don't understand what to argue to the assessors...

By the way, there is a typo in f' (the graph is correct), first term should be with minus:

$$\small{f'(x)=A(-k_{el}\cdot e^{-k_{el}\cdot x}+k_a\cdot e^{-k_a\cdot x})}$$}

and for AUC as the integral from 0 to a, "a" should go instead of x:

$$\small{A \left ( (e^{k_a \cdot a}-1)/k_a - (e^{k_{el}\cdot a}-1)/k_{el} \right )}$$

» I’m referring to the EMA’s guideline. Too lazy to Google-translate the ones in Russian.

Do not bother yourself, EAEC experts had already translated it: "Количество отобранных образцов также должно быть достаточным, чтобы обеспечить надежную оценку длительности экспозиции. Это достигается, когда AUC(0–t) перекрывает не менее 80 процентов от AUC(0–∞)."
Though the statement is not scientifically based it is still in the list of regulator's requirements. So in case if some problems with the "80% covering rule" we have to justify somehow that the validity of the study should not be called into question - that's what I've asked about.

» Therefore, the FDA does not have such a bizarre “AUC0–t ≥ 80% AUC0–∞ rule

By the way, was this question ever discussed on the conferences on harmonization?

» ...71 h → AUC0–71...

Usually the last sampling point divides completely by 12, so I may expect 48 to be the last sampling point or may be 60, but who is so crazy to leave 71 as the last point?
But there arising another interesting situation: imagine there is a IR drug with T1/2 equals to 18 hours. 4*T1/2=72 so we can leave 72 hours as the last sampling point. Which of the two parameters AUClast or AUC72 should be used to choose the best strategy to confirm BE in this case? At first sight they should be equal but this is not true. The NCA software (like Phoenix) uses AUCpartial to calculate AUC72, so for 72 hours it would be equal to AUCall but not AUClast! For some subjects the last sample could be below LLOQ, for them AUCall>AUClast with an area of triangle.

"Being in minority, even a minority of one, did not make you mad"

### Complete thread:

Admin contact
21,086 posts in 4,398 threads, 1,468 registered users;
online 3 (0 registered, 3 guests [including 3 identified bots]).
Forum time: Wednesday 02:09 CEST (Europe/Vienna)

When puzzled, it never hurts to read the primary documents
a rather simple and self-evident principle that has, nonetheless,
completely disappeared from large sectors
of the American experience.    Stephen Jay Gould

The Bioequivalence and Bioavailability Forum is hosted by
Ing. Helmut Schütz