Bioequivalence and Bioavailability Forum

Dear all,

in the new EMA-modified release guideline is stated, that for all phases partial AUC's, Cmax and tmax should be calculated. The time point for truncationing should be based on the PK-Profile and should be specified in the study protocol.

Considering following biphasic-case (biphasic tablet and biphasic PK-Profiles):
peak 1 (first tmax) around 2 hours, peak 2 about 6 hours, local minimum about 4 hours.

First, there are two possible cut-off time points:
- 2 h (as early exposure - FDA)
- 4 h (for separating the two phases as shown in the profile)

In my Opinion the 4 h as cutoff time-point is the right one, because it is - in contrast to an 2 h cutt-off time point - possible to determine the first Cmax appropriately.

Second, there are two different ways to define the Cmax of the phases (cutoff is 4 h, next blood sampling time point 4.5h) in accordance to the guideline :
- Cmax(0-4h) and Cmax(4h - t)
- Cmax(0-4h) and Cmax (4.5h - t)

If the profiles are 'as expected', the results are of the two approaches are the same. But if there are some 'not expected' profiles (for example only one peak), Cmax(0-4h) and Cmax(4h - t)could be the same (4h-)value.

From scientific point of view, i would prefer: Cmax(0-4h) and Cmax (4.5h - t). But in studies i would prefer the other approach.

What is your opinion to these issues ?

Best regard

BEman

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Edit: Category changed. [Helmut]