Karthikeyan
☆

India,
2013-08-27 13:54

Posting: # 11355
Views: 6,908

## 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).

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.

Thanks,

K@K

Edit: Category changed. [Helmut]
Helmut
★★★

Vienna, Austria,
2013-08-27 14:44

@ Karthikeyan
Posting: # 11356
Views: 6,202

## 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

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Dr_Dan
★★

2013-08-27 15:39

@ Karthikeyan
Posting: # 11358
Views: 6,147

## Russian Guidance – PK Data assay

Dear K@K
Regarding 6.1: I guess the Russian guidance refers to something like partialAUC.

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
★★★

Vienna, Austria,
2013-08-27 16:31

@ Dr_Dan
Posting: # 11359
Views: 6,142

## Russian Guidance – PK Data assay

Hi Dan & K@K,

» Regarding 6.1: I guess the Russian guidance refers to something like partialAUC.
» 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

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Dr_Dan
★★

2013-08-27 16:56

@ Helmut
Posting: # 11360
Views: 6,120

## 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
★★★

Vienna, Austria,
2013-08-27 17:37

@ Dr_Dan
Posting: # 11361
Views: 6,258

## 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”.

» 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

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
mittyri
★★

Russia,
2013-08-28 09:51

@ Helmut
Posting: # 11367
Views: 6,079

## 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
★★★

Vienna, Austria,
2013-08-28 14:32

@ mittyri
Posting: # 11371
Views: 6,047

## 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

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Helmut
★★★

Vienna, Austria,
2013-08-28 17:42

@ Dr_Dan
Posting: # 11372
Views: 6,122

## Partial AUC?

Hi Dan,

» 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.

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

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Dr_Dan
★★

2013-08-28 21:08

@ Helmut
Posting: # 11375
Views: 6,091

## 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
☆

India,
2013-08-29 14:04

@ Dr_Dan
Posting: # 11380
Views: 5,928

## Partial AUC?

Thank you all for your response.

regards,
K@K
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