Originators | generics (Cmin | Cτ) [NCA / SHAM]

posted by Helmut Homepage – Vienna, Austria, 2019-02-04 13:18  – Posting: # 19856
Views: 3,060

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:angry:
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 Lászlós: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)? :confused:

In my understanding, yes.

  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 resource.
  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?” :-D

Cheers,
Helmut Schütz
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