Bioequivalence and Bioavailability Forum • Russian Guidance

Karthikeyan
☆

India,
2013-08-27 15:54
(3884 d 17:55 ago)

Posting: # 11355
Views: 9,428

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
★★★

Vienna, Austria,
2013-08-27 16:44
(3884 d 17:06 ago)

@ Karthikeyan
Posting: # 11356
Views: 8,277

Plateau-time etc.

Post reply

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?

t_75% is the “Plateau time” – sometimes also called “POT-75” (Peak Occupancy Time 75%). The other metric is somewhat unusual. First calculate C_av = AUC_τ/τ and then the time interval where C ≥C_av.

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Helmut Schütz

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Dr_Dan
★★

Germany,
2013-08-27 17:39
(3884 d 16:10 ago)

@ Karthikeyan
Posting: # 11358
Views: 8,219

Russian Guidance – PK Data assay

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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
★★★

Vienna, Austria,
2013-08-27 18:31
(3884 d 15:18 ago)

@ Dr_Dan
Posting: # 11359
Views: 8,235

Russian Guidance – PK Data assay

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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” t_75% 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.

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

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Dr_Dan ★★ Germany, 2013-08-27 18:56 (3884 d 14:53 ago) @ Helmut Posting: # 11360 Views: 8,182	t75% Post reply
	Hi Helmut ❝ the plateau time t_75% 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 C_max but failing with regard to t_75%? I guess not, right? Kind regards Dan — Kind regards and have a nice day Dr_Dan

Helmut
★★★

Vienna, Austria,
2013-08-27 19:37
(3884 d 14:12 ago)

@ Dr_Dan
Posting: # 11361
Views: 8,444

t75%

Post reply

Hi Dan,

❝ ❝ the plateau time t_75% 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 C_max 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 C_max but failing with regard to t_75%?

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

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

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mittyri
★★

Russia,
2013-08-28 11:51
(3883 d 21:58 ago)

@ Helmut
Posting: # 11367
Views: 8,125

t75%

Post reply

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 C_max but failing with regard to t_75%?

❝

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

According russian guide t_75% 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 16:32
(3883 d 17:18 ago)

@ mittyri
Posting: # 11371
Views: 8,148

t75% (reporting only?)

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Hi mittyri!

❝ According russian guide t_75% 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 AUC_t or AUC_∞ (AUC_τ,ss if applicable), C_max, C_max/AUC_t, C_max/AUC_∞ (or C_max/AUC_τ,ss).

❝ Would you explain this issue?

Your are closer to Russian regulators than I am. ;-)

Duno, ask them. I would say simply report t_75% etc.

—
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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Helmut
★★★

Vienna, Austria,
2013-08-28 19:42
(3883 d 14:07 ago)

@ Dr_Dan
Posting: # 11372
Views: 8,406

Partial AUC?

Post reply

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

t_max 4.5, C_max 4.736, 75%C_max 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; t_75% 1.623.

[image]

In PHX/WNL you get the area above 75%C_max (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.

—
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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Dr_Dan
★★

Germany,
2013-08-28 23:08
(3883 d 10:42 ago)

@ Helmut
Posting: # 11375
Views: 8,202

Partial AUC?

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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 16:04 (3882 d 17:45 ago) @ Dr_Dan Posting: # 11380 Views: 8,030	Partial AUC? Post reply
	Thank you all for your response. regards, K@K