Vaibhav Patil
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India,
2022-07-29 07:20
(17 d 02:12 ago)

Posting: # 23187
Views: 437
 

 Partial AUC [Regulatives / Guidelines]

For modifed release formulation (Bioequivalence of partial AUC), refer the article link https://link.springer.com/article/10.1208/s12248-012-9396-8

This elaborates:

[image]


Which part of the curve bioequivalence needs to be established, upper or lower? Is it acceptable approach for EU submission.
Helmut
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Vienna, Austria,
2022-07-29 11:04
(16 d 22:28 ago)

@ Vaibhav Patil
Posting: # 23188
Views: 381
 

 H[a]VD and MDT

Hi Vaibhav,

» For modifed release formulation (Bioequivalence of partial AUC) […]
» Comparisons of HaVD and MDT can be evaluated by nonparametric calculations
» Which part of the curve bioequivalence needs to be established, upper or lower?
» Is it acceptable approach for EU submission.

Since you posted in the category Regulatives / Guidelines and asked specifically for a European submission:
  • Both PK metrics have nothing to do with the partial AUCs mentioned in the EMA’s guideline as an option to waive the MD study. The cut-off time is τ/2, unless another one is justified. Hence, in the simple case pAUC0–τ/2 and pAUCτ/2–τ.
  • European assessors are allergic to nonparametric statistics.
    Therefore, tmax (which is ordinal) was removed from the BE-GL in 2010.
  • For none (see the funny figure). HaVD (Half Value Duration, aka Peak Occupancy Time 50 ‘POT-50’)1 is the time between intersections of a horizontal line at 50% of Cmax with the profile.
    You need to interpolate concentrations, where the method of interpolation should be consistent with the chosen calculation of AUC.
    • If you calculate the AUC by the linear trapezoidal rule (I hope you don’t), interpolate by \(\small{(1)}\). $$\small{\widehat{C}=\frac{C_1+C_2}{2}\tag{1}}$$
    • If you employ the linear-up / logarithmic down rule (my recommendation), interpolate if \(\small{C_2\geq C_1}\) by \(\small{(1)}\) and if \(\small{C_2<C_1}\) by \(\small{(2)}\). $$\small{\widehat{C}=\frac{C_1+C_2}{\log_{e}\left(\frac{C_2}{C_1}\right)}\tag{2}}$$
    If there are multiple peaks, HaVD is the sum of sections.
    The calculation of MDT is trivial. However, if there are multiple peaks, MDT is undefined.
    Only formerly in Russia and currently in Kazakhstan yet another metric, the ‘Plateau Time’2 t75% (aka Peak Occupancy Time 75 ‘POT-75’) was/is required.3
  • No, it is not acceptable. In 40 years I had only one case of any antibiotic where the primary metrics were ‘Occu­pancy Times’ (times where the concentrations ≥ numerous MICs). In this particular case AUC and Cmax were only descriptive.
Personally I agree with the ‘Two Lászlós’ and think that these metrics are valuable indeed (though I don’t concur that nonparametrics are necessary). If you want to discuss these metrics, let me know and I will move this thread to the category NCA / Sham.

PS: Why did you upload the figure seven times in the lousy JPG-format (see there)? I removed them and uploaded an 8 bit PNG including the legend instead.
PPS: A salutation in posts is polite and never hurts.


  1. Endrényi L, Tóthfalusi L. Metrics for the Evaluation of Bioequivalence of Modified-Release Formulations. AAPS J. 2012; 14(4): 813–9. doi:10.1208/s12248-012-9396-8. [image] Free full text.
  2. Steinijans VW, Sauter R, Diletti E. Shape Analysis in Single- and Multiple-Dose Studies of Modified Release Pro­ducts. In: Blume HH, Midha KK (ed’s). Bio-International 2. Stuttgart: medpharm Scientific Publishers; 1995. pp. 193–206.
  3. Shohin IE, Roshdestvenskij DA, Medvedev VYu, Komarow TN, Grebenkin DYu. Russia, Belarus & Ka­sakh­stan. In: Kanfer I. (ed). Bioequivalence Requirements in Various Global Jurisdictions. Cham: Springer; 2017. pp. 199–227.

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mittyri
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Russia,
2022-07-30 14:17
(15 d 19:16 ago)

(edited by mittyri on 2022-07-30 15:27)
@ Helmut
Posting: # 23193
Views: 271
 

 Plateau Time in Kazakhstan?

Hi Helmut,

» Only formerly in Russia and currently in Kazakhstan yet another metric, the ‘Plateau Time’2 t75% (aka Peak Occupancy Time 75 ‘POT-75’) was/is required.3
» <...>
» 3. Shohin IE, Roshdestvenskij DA, Medvedev VYu, Komarow TN, Grebenkin DYu. Russia, Belarus & Ka­sakh­stan. In: Kanfer I. (ed). Bioequivalence Requirements in Various Global Jurisdictions. Cham: Springer; 2017. pp. 199–227.

Sorry, I don't have that book to prove my opinion, but I strongly doubt that it is still applicable in Ka­sakh­stan as a member of EEU.
Appendix X for Regulations conducting BE studies within the framework of the EEU approved 2 years ago is related to modified release forms and it mimics (what a surprise!) EMA MR Guide.
I see that related to Kazakhstan links provided on the book site are pretty old.

Kind regards,
Mittyri
Helmut
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Vienna, Austria,
2022-08-01 18:44
(13 d 14:48 ago)

@ mittyri
Posting: # 23199
Views: 217
 

 Plateau Time in Kazakhstan?

Hi mittyri,

» […] I strongly doubt that it is still applicable in Ka­sakh­stan as a member of EEU.

I trust you, of course.

» Appendix X for Regulations conducting BE studies within the framework of the EEU

Do you have a copy? The site times out, regardless which browser I tried. Not even the TOR-browser with the Snowflake-plugin via a VPN worked. Is the site really down or access blocked?
The webarchive didn’t work either. The last capture is poo.

» approved 2 years ago is related to modified release forms and it mimics (what a surprise!) EMA MR Guide.

:-D

» I see that related to Kazakhstan links provided on the book site are pretty old.

Right. I had to work with what I have.

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mittyri
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Russia,
2022-08-01 21:24
(13 d 12:08 ago)

@ Helmut
Posting: # 23200
Views: 217
 

 EEU changes came into force 11.03.2021

Hi Helmut,

» » Appendix X for Regulations conducting BE studies within the framework of the EEU
»
» Do you have a copy? The site times out, regardless which browser I tried. Not even the TOR-browser with the Snowflake-plugin via a VPN worked. Is the site really down or access blocked?
» The webarchive didn’t work either. The last capture is poo.

sorry, that link was a real nightmare, seems like it is not a simple html. On EEU site there is a pdf on Russian with the list of changes. Since Appendix 10 was introduced primarily, it could be treated as is.
I've found it here, where also a zip archive could be found with a Word version of the document.

Kind regards,
Mittyri
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