Bioequivalence and Bioavailability Forum

Greeting to all (after loooong weekend on the beach )!

❝ some comments on this week’s workshop in Bonn.

Man. It's nice to be your own boss. lucky you. I used all my budget for the conference on BA/BE/BW in Budapest last May so I won't be anywhere later this year.

❝ • According to the draft MD studies might be waived under certain circumstances:

❝ — AUC_t > 90% AUC_∞ and

❝ — BE demonstrated in SD for additional PK metrics, e.g., pAUCs (C_τ under discussion).

You meant AUC_τ, not AUC_t, right? The same goes for the following procedure in your post.

Just to make sure I didn't misunderstand the PK parameters in the guideline, let's say one Reference product has to be taken twice a day so dose interval would be 12 hours. In single dose BE study let's say sampling is up to 18 hours.
Then AUC_τ is AUC_0-12 (and C_τ, in case we are allowed to use it to replace MD study in the future, would be C_{12 hours}), AUCt would be AUC_0-18.

In order to avoid MD study, I would firstly just do single dose study with all necessary PK parameters defined in the protocol such as pAUCs (assuming that AUC_0-4 and AUC_4-18 are wonderful choices for the sake of argument).

So I'd compare AUC_0-12/AUC_0-∞ to see if the ratio is >90%. If I'm lucky, then I can do ANOVA on the rest of the parameters (C_max, AUC_0-4, AUC_4-18, AUC_0-18, AUC_0-∞). And if I'm lucky again, no MD study. (ok, instaed of saying lucky I should probably use "my formulation's good" )

By the way, one doubt here.

What if AUC_τ/AUC_0-∞ is <90% for reference but >90% for test? So reference has risk of accumulation but test does not. Can we waive MD study?
I wish that we could but probably not if "less food effect contradictory to the definition of generic... " is any indication. But I'd like to hear all thoughts from forum members anyway.

While we were talking about parameter, I have another question.
Since there're several C_min to choose (predose, post dose, true C_min...), C_min was defined as "the concentration at the end of the dose interval" (in steady state). However the guideline defined the C_τ,ss as such as well. So what's the difference between them?

❝ • If the MD study passes with the conventional metrics (AUC_τ, C_max, C_min), the fact that ‘shape’ metric(s) failed in SD will not lead to rejection of the application (rationale: BE demonstrated with conventional metrics both in SD and MD).

Nice. Is this a consensus and will be written in the final guideline or just our wish?

❝ There was a short discussion whether for delayed release AUC_0-T & AUC_T-t and for prolonged release AUC_0-T & AUC_T-∞ would be sufficient (dropping the respective other AUC-metrics). No consensus was reached.

No kidding. I was under the impression that pAUC will not be required for delayed-release formulation. I remembered that Dan Seiler (or someone else?) said so during the panel discussion on the 2nd day in the Budapest conference. Or I misunderstood it? D***, that would affect many of my projects.