pAUCs, alternative metrics, alcohol [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2013-06-27 16:38 (3739 d 10:53 ago) – Posting: # 10893
Views: 18,852

Hi Shuanghe!

❝ I know the guideline said both test and reference.

❝ What I was trying to ask is if anyone mentioned this point so we might get generic product with AUCτ/AUC0-∞ is <90% for reference but >90% for test. It's a long shot I know.

Nobody raised this question. In my understanding you will get an approval, only the MD study will be mandatory. Up to you to send a comment to the EMA.

❝ OK. What about "better alcohol effect" :-D?

❝ We know in vitro dissolution with alcohol (0, 5, 10, 20%, and maybe 40% as well as FDA did) will be required and the "criterion" is "similar effect".

I didn’t take notes, so we have to wait for the presentations at EUFEP’s website. Maybe Dan does remember? In a recent line extension we were asked for 0, 5, 20, and 40% at pH 1.2 for two hours.

❝ But for alcohol, maybe "better" and "equivalent" is not that contradictory? […] for alcohol I'd say it should be allowed to have generic product release less in alcohol than reference.

I would support that.

❝ Anyone mentioned this in the discussion?

Not that I recall. However, there was a lengthy discussion whether the GL should concentrate on “intended use” or “misuse”. Food effects and alcohol-related dose dumping are different.I would say the requirement should be case-by-case and not a general one. Another point to comment.

❝ ❝ Imagine two applications: :blahblah:

❝ When you put it this way, it's crystal-clear.

Sometimes I fail to make myself clear in the first place. Sorry.

❝ […] No MD study for DR dosage form, that's clear from the guideline (unless they change their mind of course).

❝ What I meant to say was that Line 800 indicated that Cmax, AUC0-t, AUC0-∞ and partialAUC will be required for MR formulation in single dose study. My argument is that only the former 3 parameters should be required for DR formulation and all 4 parameters required for prolonged-release formulation in single dose study. That's impression I got from Budapest conference.

Gotcha. Does partialAUC in line 800 mean only the first one (singular; like the FDA’s/TGD’s early exposure)? Seems so, because for prolonged release (line 805) the EMA uses the plural: “early and terminal partialAUCs”. Another ambiguity which calls for a comment. There was some dis­cussion whether this section should be extended to:

“AUC(0-t), AUC(0-∞), Cmax and a representative parameter of the shape of the curve, e.g., (early and terminal partialAUCs)

Depending on the formulation pAUCs might not be optimal metrics. Example: Flat profiles with ill-defined tmax. Henning and I voted for the plateau time1 or HVD.2 Unfortunately we have only few published data of pAUCs (especially AUCT-t; exception: some multiphasic for­mu­la­tions). On the other hand for MR theophylline we have a lot of data about t75%. Hen­ning gave the FDA’s example of requiring all MR studies to be performed in a replicate design in order to explore the subject-by-formulation interaction. This requirement was in force for ~two years. After reviewing the data, the FDA concluded that S×F is unlikely and lifted the requirement. Hen­ning suggested to have additional metrics3 as exploratory ones for a limited period of time (should not lead to rejecting an application if failed) and after reviewing the performance clari­fy­ing requirements. No need to update the GL; could be done in the Q&A document. Perso­nally I’m skeptic whether the EMA will follow this track…

❝ ❝ However, this question was raised. The main concern is AUCT-∞ instead of AUCT-t for PR. Higher variability and not consistent with US/CAN. Whatever the outcome will be (and I don’t think MD will be required for DR) it will affect projects starting 1½ years from now (my guess about the timeline).

❝ Not sure if I understood your message correctly, you mean that pAUC (in single dose study) will be required for DR formulation as well?

For DR I guess only the first pAUC will be required (line 800); see also what I wrote above.

  1. Plateau time (t75%) or Peak Occupancy Time (POT-25): Time period during which concentrations are within 25% of Cmax.
  2. Half-value duration (HVD), POT-50: Time period during which con­cen­trations are within 50% of Cmax. According to László Endrényi (EUFEPS, Barcelona 2010) more stable than POT-25.
  3. Besides #1 and #2, other metrics suggested in Barcelona:
    Capical: Average of concentrations within POT.
    AUCapical: Average of AUCs within POT.
    MDT: Median duration time.
    For the cut-off time point of early exposure Endrényi et al. (1998) suggested the earlier tmax calculated for each subject.

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