Bioequivalence and Bioavailability Forum • Cmin really gone. tmax reappeared

Cmin really gone. tmax reappeared - but how? [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2010-02-02 00:30 (5616 d 07:21 ago) – Posting: # 4688
Views: 24,552

Dear D Labes!

❝ ❝ "no apparent difference in median t_max and its variability").

❝

❝ What ever this means. Report the values, give some descriptive statistics and forget.

❝

❝ I find it very strange that the abhorrence for non-parametric methods leads to such a featureless evaluation guidance, even in the case t_max is clinically relevant.

❝ Implicitly this accepts that t_max can only be analyzed non-parametrically, but "... Non-parametric analysis is not acceptable. ...". Thus we have no statistical method left.

Exactly. OK, the median is mentioned. What is “no apparent difference”? Since non-parametrics are not acceptable - how far should we go? Damn, why is it not acceptable to use the right method? Are box plots acceptable? If yes, which ones? Or should we go with the weird plots suggested by

Sauter R, Steinijans VW, Diletti E, Böhm E and H-U Schulz
Presentation of results from bioequivalence studies
Int J Clin Pharm Ther Toxicol 30/Suppl1, S7-S30 (1992)

❝ ❝ C_ss,min has vanished.

❝

❝ But I noticed yet this is only true for immediate release products.

❝

❝ Thus we have the situation that we need distinct sets of PK parameters for multiple dose studies depending on the product characteristics immediate or modified release. The question is: Why?

Oh, this doesn’t worry me. MR products are by their design more complicated to assess. For DR products I would look at t_lag, for some products (double pulse) I would use partial AUCs (first part, second part), for CR with flip-flop-PK or transdermals my primary metric is AUC_inf (not AUC_t!), etc. IMHO, the one-size-fits-all concept is not applicable to MR products.

It would be of interest whether scaling for C_max is acceptable for MR products also - and by analogy for C_min. Time to update the MR guideline (was once announced for 2010). BTW, I’m planning for a replicate steady-state study just to see.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Complete thread:

EMA BE guideline - final version Ohlbe 2010-01-28 18:31 [Regulatives / Guidelines]
- Final version published Helmut 2010-01-29 14:29
  - Final version published ElMaestro 2010-01-29 17:02
    - Statistix Helmut 2010-01-29 17:30
      - Statistix ElMaestro 2010-01-29 18:11
    - Calories ;-) Helmut 2010-01-29 19:22
      - Calories ;-) ElMaestro 2010-01-29 20:43
        
        Calories ;-) Helmut 2010-01-29 21:08
      - Variable calories d_labes 2010-02-01 12:05
    - ANOVA only - no doubts Helmut 2010-02-10 23:41
      - ANOVA only - no doubts ElMaestro 2010-02-12 21:09
  - Final EMA oracle d_labes 2010-02-01 11:53
    - Final EMA oracle Helmut 2010-02-01 12:28
    - Final EMA oracle ElMaestro 2010-02-01 12:50
      - More then two EMA oracles d_labes 2010-02-01 13:30
        
        Less of an issue ElMaestro 2010-02-01 15:29
        
        Less or More of an issue d_labes 2010-02-01 16:53
        
        Less or More of an issue ElMaestro 2010-02-01 17:22
        
        Effective with 1 Aug 2010 Helmut 2010-02-02 00:55
        Bias? ElMaestro 2010-02-04 11:27
        
        Bias? Helmut 2010-02-05 02:03
        
        Bias? ElMaestro 2010-02-05 09:33
        
        Bias? Helmut 2010-02-05 10:21
        
        Bias? d_labes 2010-02-05 13:59
        Bias? ElMaestro 2010-02-05 16:00
        
        Bias? Helmut 2010-02-05 19:14
      - Final EMA oracle Helmut 2010-02-01 13:43
        
        Final EMA oracle ElMaestro 2010-02-01 14:54
        
        Final EMA oracle d_labes 2010-02-01 15:20
        
        Teaching Helmut 2010-02-01 16:07
  - Cmin really gone? tmax reappeared? d_labes 2010-02-01 14:02
    - Cmin really gone. tmax reappeared - but how?Helmut 2010-02-01 23:30
  - Interpol or not d_labes 2010-02-01 14:52
    - Interpol! Helmut 2010-02-02 00:02
      - Interpol! ray_be 2010-02-03 18:31
        
        WinNonlin/Phoenix extrapolation to t=tau Helmut 2010-02-03 20:26
  - Meta-analysis Helmut 2010-02-07 17:41
  - Final version published Panks.79 2010-03-08 07:22
    - Cmin for MR-formulations? Helmut 2010-03-08 18:16
      - Cmin for MR-formulations? Marcel 2010-04-23 10:09
        
        MR-Guideline? Helmut 2010-04-23 12:34
- Overview of comments published Helmut 2010-02-10 18:33
  - Comments commented d_labes 2010-02-11 08:19
  - Definition of Cmin by EMEA Ravi 2010-03-13 12:05
    - The EMA’s Cmin & WinNonlin Helmut 2010-03-13 12:52