Bioequivalence and Bioavailability Forum

Hi Nastia,

atavism ≠ anachronism.

❝ […] I thought that in the battle C_min vs C_trough, C_trough 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 Lászlós:¹

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

❝ According to wikipedia pharmacokinetics, for example, C_min is C_trough (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 C_τ if there are time deviations (t_last ≠ 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 C_min (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, C_τ – which the EMA considers to be “easier to determine”² (MR-GL Section 6.8.1.2). Why C_τ should be easier to determine than C_min is beyond me.

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

In my understanding, yes.

• C_ss,min: Hybrid application (MR vs. IR: Section 5.1.1).
  
• C_τ,ss: Generic application (MR vs. MR: Section 6.8.1.2).

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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. 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?”