Karthikeyan
Junior

India,
2013-08-27 13:54

Posting: # 11355
Views: 6,544
 

 Russian Guidance – PK Data assay [NCA / SHAM]

Dear all,

i was going through the PK data assay in Russian guidance and i could not understand the following

6.1. Single dosing of pharmaceutical product
Further analysis of pharmacokinetic data assuming calculation of individual; rates AUCt or AUC∞ … for usual forms, and for prolonged-release forms – duration of time when drug substance concentration is 75% higher the Cmax (T>75%Cmax). :confused:

6.2. Repeat dosing of pharmaceutical product
For prolonged-released forms duration of time period is calculated when drug substance concentration is higher than mean steady-state value Css (T>Css), and T>75%Cmax. :confused:

Please help me out in understanding this.
Thanks,

K@K


Edit: Category changed. [Helmut]
Helmut
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Vienna, Austria,
2013-08-27 14:44

@ Karthikeyan
Posting: # 11356
Views: 5,895
 

 Plateau-time etc.

Hi K@K,

» For prolonged-released forms duration of time period is calculated when drug substance concentration is higher than mean steady-state value Css (T>Css), and T>75%Cmax.

What do you not understand? The PK metrics as such, or why they are mentioned in the guideline, or what?

t75% is the “Plateau time” – sometimes also called “POT-75” (Peak Occupancy Time 75%). The other metric is somewhat unusual. First calculate Cav = AUCτ/τ and then the time interval where C ≥Cav.

Cheers,
Helmut Schütz
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Dr_Dan
Senior

2013-08-27 15:39

@ Karthikeyan
Posting: # 11358
Views: 5,839
 

 Russian Guidance – PK Data assay

Dear K@K
Regarding 6.1: I guess the Russian guidance refers to something like partialAUC.
What do you think about this parameter?:

partialAUC(0-Tmax)+(Tmax-T75%Cmax)

Regarding 6.2, IMHO it does not make sense for an individual PK parameter to have a reference to mean values. So I agree, this is very confusing. Partial AUC without initial absorption phase until mean steady state concentration is reached until decline after Tmax to individual 75%Cmax values? This does not make sense, right?
Kind regards
Dan

Kind regards and have a nice day
Dr_Dan
Helmut
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Vienna, Austria,
2013-08-27 16:31

@ Dr_Dan
Posting: # 11359
Views: 5,836
 

 Russian Guidance – PK Data assay

Hi Dan & K@K,

» Regarding 6.1: I guess the Russian guidance refers to something like partialAUC.
» What do you think about this parameter?:
» partialAUC(0-Tmax)+(Tmax-T75%Cmax)

Interesting formula. No sure whether it “works” – intuitively I don’t think so. Last year in Moscow at two occassions my Russian colleagues were clear about the definiton. BTW, the “Plateau Time” t75% is a rather old PK metric.* László Endrényi in his presentations prefers “Peak Occupancy Time” (POT-75).

» Regarding 6.2, IMHO it does not make sense for an individual PK parameter to have a reference to mean values.

Oops, I didn’t see that. Very strange. This may be a translation issue as well. I have three English translations of the Russian GL differing in many points. :-|


  • Steinijans VW, Sauter R, Diletti E. Shape Analysis in Single- and Multiple-Dose Studies of Modified Release Products. In: Blume HH, Midha KK, editors. Bio-International 2. Stuttgart: medpharm Scientific Publishers; 1995. p. 193–206.

Cheers,
Helmut Schütz
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Dr_Dan
Senior

2013-08-27 16:56

@ Helmut
Posting: # 11360
Views: 5,826
 

 t75%

Hi Helmut
» the plateau time t75% is a rather old PK metric
maybe I am too young, I never heard of it...;-)
However, what would be the advantage of this parameter? Would it be possible to be bioequivalent with regard to AUC and Cmax but failing with regard to t75%? I guess not, right?
Kind regards
Dan

Kind regards and have a nice day
Dr_Dan
Helmut
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Vienna, Austria,
2013-08-27 17:37

@ Dr_Dan
Posting: # 11361
Views: 5,942
 

 t75%

Hi Dan,

» » the plateau time t75% is a rather old PK metric
» maybe I am too young, I never heard of it... ;-)

Die Gnade der späten Geburt.

» However, what would be the advantage of this parameter?

Useful for multiple peaks (see this example) and “flat profiles”. If you compare Cmax that might be apples-and-oranges-statistics. Actually Steinijans & Co. introduced this metric for prolonged release theophylline (see also the book by Hauschke, Steinijans, and Pigeot). I those dark ages there was even a saying:

“Volker Steinijans and his wife Theophylline”. :-D


» Would it be possible to be bioequivalent with regard to AUC and Cmax but failing with regard to t75%?

Yes, it is, The Lászlós (who else?) have shown that. Will excavate the reference.

Cheers,
Helmut Schütz
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mittyri
Senior

Russia,
2013-08-28 09:51

@ Helmut
Posting: # 11367
Views: 5,777
 

 t75%

Hi Helmut, Dan & K@K!

I have similar questions reading this guide.

There's no translation issue in chapter 6.2. In Russian we have the same.

» » Would it be possible to be bioequivalent with regard to AUC and Cmax but failing with regard to t75%?
»
» Yes, it is, The Lászlós (who else?) have shown that. Will excavate the reference.

According russian guide t75% is calculated (chapter 6.1).
So the question is: what can we do with this data?
As you can see in chapter 7 (Statistical evaluation of bioequivalence) this parameter isn't used.
Would you explain this issue?

Kind regards,
mittyri

Kind regards,
Mittyri
Helmut
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Vienna, Austria,
2013-08-28 14:32

@ mittyri
Posting: # 11371
Views: 5,752
 

 t75% (reporting only?)

Hi mittyri!

» According russian guide t75% is calculated (chapter 6.1).
» So the question is: what can we do with this data?
» As you can see in chapter 7 (Statistical evaluation of bioequivalence) this parameter isn't used.

Interesting, didn’t notice that before! Chapter 6.1 and 6.2 calls for the T/R ratios of these PK metrics and Chapter 7 calls for BE assessment of AUCt or AUC (AUCτ,ss if applicable), Cmax, Cmax/AUCt, Cmax/AUC (or Cmax/AUCτ,ss).

» Would you explain this issue?

Your are closer to Russian regulators than I am. ;-) Duno, ask them. I would say simply report t75% etc.

Cheers,
Helmut Schütz
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Helmut
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Vienna, Austria,
2013-08-28 17:42

@ Dr_Dan
Posting: # 11372
Views: 5,803
 

 Partial AUC?

Hi Dan,

» What do you think about this parameter?:
» partialAUC(0-Tmax)+(Tmax-T75%Cmax)

Not sure which time point(s) you mean for truncation. See the following example:
 0.5167 BQL
 1      1.144
 1.5    2.399
 2      3.226
 2.5    3.236
 3      2.943
 3.5    2.776
 4      3.393
 4.5    4.736
 5      3.934
 6      3.387
 9      1.643
12.0333 0.717
16.0167 0.231

tmax 4.5, Cmax 4.736, 75%Cmax 3.552. In Phoenix/WinNonlin-style that would mean linear inter­po­la­tion in the increasing sections () and loglinear in the decreasing sections ().* Therefore, the first intersection is at 4.059 and the second one at 5.682; t75% 1.623.

[image]

In PHX/WNL you get the area above 75%Cmax (0.774) and below (28.101) but I don’t think that this is what you had in mind.


  • Irrespective of which trapezoidal rule is set. The same is true for partial AUCs.

Cheers,
Helmut Schütz
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Dr_Dan
Senior

2013-08-28 21:08

@ Helmut
Posting: # 11375
Views: 5,796
 

 Partial AUC?

Hi Helmut

» but I don’t think that this is what you had in mind.

correct. This makes no sense. I thought of AUC0-tmax + AUCtmax-t75%Cmax. I hope you understand me now better. In other words the area under the curve from the beginning (=start of absorption) until the time point after tmax when 75% of Cmax are reached. Oh god, how difficult to describe....
LG
Dan

Kind regards and have a nice day
Dr_Dan
Karthikeyan
Junior

India,
2013-08-29 14:04

@ Dr_Dan
Posting: # 11380
Views: 5,629
 

 Partial AUC?

Thank you all for your response.

regards,
K@K
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