Helmut
★★★

Vienna, Austria,
2011-03-08 15:30

Posting: # 6728
Views: 7,824

## Steady state: Cmin / PTF [NCA / SHAM]

Dear all,

at the “EUFEPS BABP Network Open Discussion Forum” members of EMA’s PK-group unambigiously made clear what they mean by Cmin in steady state, namely the concentration at the end of the dosing inter­val. See also the presentation (slides 31–34) by Christoph Baumgärtel (AGES, raporteur for the MR-GL). See also a previous thread.

It’s important to check your software. If you use PHX/WNL, forget Cmin, Cavg, and Fluctuation% in the output – which are based on the global minimum within the dosage interval. I’ll ask Pharsight for an update – please do so as well, in order to speed things up.
In the meantime consider setting up a workaround by two Custom Column Transformations (to NCA Results, Final Parameters Pivoted):
New Column Name Tau
Formula          24 ← the numeric value of the dosing interval

New

New Column Name PTF
Formula          100*(Cmax-Clast)/(AUCtau/Tau)

I have no idea yet how to deal with missing values at the end of the dosing interval (tlast # τ). If you are able to estimate λz and tick [×] Intermediate Output in the Model Settings of NCA you get additionally the intercept (in log-scale) of the regression – which would allow to calculate an estimated Ĉmin value at t=τ. But this value is only given in the Core output (not available as a variable in the NCA Results)…

Cheers,
Helmut Schütz

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

UK,
2012-02-06 14:00

@ Helmut
Posting: # 8060
Views: 5,784

## Steady state: Cmin / PTF

sorry for the late comment only just saw this;

» If you are able to estimate λz and tick [×] Intermediate Output in the Model Settings of NCA you get additionally the intercept (in log-scale) of the regression – which would allow to calculate an estimated Ĉmin value at t=τ. But this value is only given in the Core output (not available as a variable in the NCA Results)…

The predicted Clast is extractable from the Summary table; here's a simple example with an Inner Join. See how sample time is JOINED AS Tlast, so obviously only truly appropriate where Tlast=Tau.

/********* Begin Mappings ********************/ Worksheet 1 : Project.Workflow.NCA.Final Parameters Pivoted   Sort : Subject, Tlast   Source Column : Worksheet 2 : Project.Workflow.NCA.Summary Table   Sort : Subject, Time [hr ]   Source Column : Predicted [ng/mL] Sort Map : (Internal) /****************** End Mappings   ****************/

Simon
Senior Scientific Trainer
Pharsight - A Certara™ Company
https://www.certara.com/training/training-your-way
https://support.certara.com/forums/
Problems are not stop signs, they are guidelines. Robert H. Schuller
Helmut
★★★

Vienna, Austria,
2012-02-06 14:24

@ SDavis
Posting: # 8062
Views: 5,853

## Steady state: Cmin / PTF

Hi Simon!

» The predicted Clast is extractable from the Summary table; here's a simple example with an Inner Join. See how sample time is JOINED AS Tlast, so obviously only truly appropriate where Tlast=Tau.

Nice method. Incomplete, isn’t it?
You need to sort also on Formulation and Period, map Clast to Source Column of Worksheet 1, map Sequence to Source Column in one of the worksheets, set ☑ Inner Joint and edit cells B1 and B5 of the Sort Map from …
  Worksheet 1 Sorts  Worksheet 2 Sorts 1 Tlast 2 Subject            Subject 3 Period             Period 4 Formulation        Formulation 5                    Time
… to
  Worksheet 1 Sorts  Worksheet 2 Sorts 1 Tlast              Time 2 Subject            Subject 3 Period             Period 4 Formulation        Formulation

Unfortunately tlast in a cross-over multiple dose study (at least in the first period) τ; the last sample is generally taken 5–10 minutes before the next administration. I would suggest using one of two methods (see here, slides 35, 48–50). Personally I prefer method (1); method (2) is PHX/WNL’s method in the calculation of AUCτ. Note that if the last sample was taken exactly at τ (f.i. in the second period), no correction will be done by both methods (i.e., the estimated Cmin = Clast and AUCτ = AUClast), since the time difference = 0 and ℯ0 = 1.

Cheers,
Helmut Schütz

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

Russia,
2019-02-03 22:25

@ Helmut
Posting: # 19853
Views: 2,632

## Is Cmin an atavism or not?

Dear all!

I searched through the forum and found plenty of themes dedicated to the difference between Cmin and Ctrough (Ctau). I thought that in the battle Cmin vs Ctrough, Ctrough was the winner. So that in the calculation of fluctuation (Peak-to-trough) and swing as well. According to wikipedia pharmacokinetics, for example, Cmin is Ctrough (was happy to see Helmut's graph there).

I finally upgraded to PHX/WNL 8.1 and see in the output the both versions of calculation: swing and swing_tau, Fluctuation and Fluctuation_tau. Some may think that PHX/WNL wants to show tollerance and include everyone's points of view... But, finally, what parameters should we include in the report according to official regulator's point of view? Or it depends on whether reference is IR or MR (see here)?

"We are such stuff as dreams are made on, and our little life, is rounded with a sleep"
Helmut
★★★

Vienna, Austria,
2019-02-04 13:18

@ Astea
Posting: # 19856
Views: 2,621

## Originators | generics (Cmin | Cτ)

Hi Nastia,

atavism anachronism.

» […] I thought that in the battle Cmin vs Ctrough, Ctrough was the winner. So that in the calculation of fluctuation (Peak-to-trough) and swing as well.

Ha-ha, by saying A we mean B. Newspeak
IMHO, fine examples of swing: #1, #2, #3, #4. Whoever invented swing as a PK metric should be hanged, cut off, and quartered. To quote the two Lászlos:1

%Swing was found to be very sensitive to changes and errors in Cmin and was, therefore, considered to be an awkward metric.

» According to wikipedia pharmacokinetics, for example, Cmin is Ctrough (was happy to see Helmut's graph there).

Well, I tried to make it simple there.

» I finally upgraded to PHX/WNL 8.1 …

So did I, yesterday. Interesting.

» … and see in the output the both versions of calculation: swing and swing_tau, Fluctuation and Fluctuation_tau. Some may think that PHX/WNL wants to show tollerance and include everyone's points of view...

Yep. I insisted to have both in the new version. Not everybody is experienced enough to calculate Cτ if there are time deviations (tlast  τ) or the last observation is missing.

» But, finally, what parameters should we include in the report according to official regulator's point of view?

If you read the EMA’s MR-GL closely you will discover that rules for originators and generic companies are different! For originators it is the true Cmin (minimum anywhere within τ) – and this is the only one given in textbooks of PK for ages. Makes sense because this  is  might be related to the effect.
On the other hand, for generics similarity of the formulation is more important (don’t want to start an argument, why). Hence, Cτ – which the EMA considers to be “easier to determine”2 (MR-GL Section 6.8.1.2). Why Cτ should be easier to determine than Cmin is beyond me.

» Or it depends on whether reference is IR or MR (see here)?

In my understanding, yes.
• Css,min: Hybrid application (MR vs. IR: Section 5.1.1).
• Cτ,ss: Generic application (MR vs. MR: Section 6.8.1.2).

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.
2. Picky: “Easier” is a comparative. With few exceptions (absolute comparatives like “higher education”) using a comparative without a comparison is bad grammar.
If someone tells me that sumfink is easier, I always reply “Easier than what?”

Cheers,
Helmut Schütz

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

Russia,
2019-02-04 13:51

@ Helmut
Posting: # 19859
Views: 2,600

## Down with Big Brother

Dear Helmut!

Through "atavism" I meant something like a tail in human body - smthg that should be dissapeared while evolution.

It turns out I was totally confused... May I clarify once more: for non-comparative PK trials of IR do we need only classical global Cmin? Аnd for MR Ctrough (as it is written in the article)?

"We are such stuff as dreams are made on, and our little life, is rounded with a sleep"
Helmut
★★★

Vienna, Austria,
2019-02-04 14:43

@ Astea
Posting: # 19860
Views: 2,564

## Down with Big Brother

Hi Nastia,

» Through "atavism" I meant something like a tail in human body - smthg that should be dissapeared while evolution.

OK, but atavism works the other way ’round. A baby born with a tail. An anachronism would be using a sliding rule instead of pocket calculator.

» May I clarify once more: for non-comparative PK trials of IR do we need only classical global Cmin?

Not sure what you mean by “non-comparative PK trial of IR”. For IR you don’t need it at all (Cmin,ss was suggested in the draft IR-GL but didn’t make it to the final version). In the comments we find the nice apples-and-oranges sentence:

“By Cmin,ss we mean the concentration at the end of the dosage interval, i.e. Ctrough.”

Given. Common understanding: Cmin,ss = Ctrough, which is  Cτ,ss in case of a lag-time. Even without a lag-time due to variability Cmin,ss can be observed at the beginning or the end of the dosing interval. Sigh.

In a hybrid application (no MR on the market; comparison to IR or even a solution) I would say Css,min. BTW, currently I’m dealing with a hybrid for Canada. It’s a biphasic product with a lag-time. After some to-and-fro: Both Css,min and Cτ,ss. Oh dear…

» Аnd for MR Ctrough (as it is written in the article)?

Yep – if the two Lászlos meant Cτ,ss.

Cheers,
Helmut Schütz

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

Russia,
2019-02-04 15:13

@ Helmut
Posting: # 19861
Views: 2,545

## thoughtcrime

» Common understanding: Cmin,ss = Ctrough, which is  Cτ,ss in case of a lag-time. Even without a lag-time due to variability Cmin,ss can be observed at the beginning or the end of the dosing interval. Sigh.

Come on! By def Ctrough occurs at the end of dosing interval... I give up... It is impossible to distinguish!

"We are such stuff as dreams are made on, and our little life, is rounded with a sleep"
Helmut
★★★

Vienna, Austria,
2019-02-04 15:34

@ Astea
Posting: # 19862
Views: 2,530

## blackwhite

Hi Nastia,

» […] By def Ctrough occurs at the end of dosing interval... I give up... It is impossible to distinguish!

Veto!
Look up trough in an English dictionary. A kind of minimum, right? The minimum (hence in the textbooks “Cmin”) can occur anywhere in the profile. If you have no lag-time the chance to observe it at the beginning and the end is 50% each (by definition).
I’m fine with the term Cτ,ss cause it is unambigous. IMHO, the term Ctrough shouldn’t be used at all.

Définissez les termes, vous dis-je, ou jamais nous ne nous entendrons.

Define your terms, you will permit me again to say, or we shall never understand one another.
Voltaire (Miracles, 1764)

Cheers,
Helmut Schütz

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

Russia,
2019-02-04 15:53

@ Helmut
Posting: # 19863
Views: 2,513

## animal farm

Dear Helmut!

» Look up trough in an English dictionary. A minimum, right?

Hmm, get what you ask for trough

Anyway thank you for the clarification! Now it is more transparant for me. I will use Cτ,ss and Cmin.

"We are such stuff as dreams are made on, and our little life, is rounded with a sleep"
Bioequivalence and Bioavailability Forum |  Admin contact
19,817 posts in 4,200 threads, 1,361 registered users;
online 14 (0 registered, 14 guests [including 11 identified bots]).
Forum time (Europe/Vienna): 16:36 CEST

A big computer, a complex algorithm and a long time
does not equal science.    Robert Gentleman

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
Ing. Helmut Schütz