SD vs. MD, partial AUCs [Regulatives / Guidelines]

posted by Shuanghe  – Spain, 2013-06-25 19:22 (3741 d 08:51 ago) – Posting: # 10879
Views: 18,725

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

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

Man. It's nice to be your own boss. :ok: 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:

❝ — AUCt > 90% AUC and

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

You meant AUCτ, not AUCt, 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 AUCτ is AUC0-12 (and Cτ, in case we are allowed to use it to replace MD study in the future, would be C12 hours), AUCt would be AUC0-18.

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 AUC0-4 and AUC4-18 are wonderful choices for the sake of argument).

So I'd compare AUC0-12/AUC0-∞ to see if the ratio is >90%. If I'm lucky, then I can do ANOVA on the rest of the parameters (Cmax, AUC0-4, AUC4-18, AUC0-18, AUC0-∞). And if I'm lucky again, no MD study. (ok, instaed of saying lucky I should probably use "my formulation's good" :-D)

By the way, one doubt here.

What if AUCτ/AUC0-∞ 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... :blahblah:" 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 Cmin to choose (predose, post dose, true Cmin...), Cmin was defined as "the concentration at the end of the dose interval" (in steady state). However the guideline defined the Cτ,ss as such as well. So what's the difference between them?

If the MD study passes with the conventional metrics (AUCτ, Cmax, Cmin), 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 AUC0-T & AUCT-t and for prolonged release AUC0-T & AUCT-∞ would be sufficient (dropping the respective other AUC-metrics). No consensus was reached.

No kidding.:surprised: 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? :confused: D***, that would affect many of my projects.

All the best,

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