Cmin (EU) [Surveys]

posted by Helmut Homepage – Vienna, Austria, 2009-12-21 13:08 (4235 d 09:50 ago) – Posting: # 4517
Views: 13,127

Dear colleagues,

since I saw a couple of deficiency letters concerning Cmin in the recent past, I want to start a little survey and discussion. The BE-Draft (2008) states (lines 558-559):

For studies to determine bioequivalence at steady state AUCtau, Cmax,ss, and Cmin,ss should be analysed using the same acceptance interval as stated above.

and in lines 551-552:

For these parameters the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of 80-125%.

Lines 561-562 state:

[…] for highly variable drugs the acceptance interval for Cmax may in certain cases be widened (see section 4.1.10).

I would say the same rationale for widening the acceptance range (clinical justification, high variability) for Cmax is justifiable for Cmin.
  1. How do you define Cmin in steady state?
    1. Minimum concentration within the profile
    2. Pre-dose concentration
    3. Last concentration within the dosing interval
    4. Minimum concentration within time of administration and tmax
    5. Additional question: your rationale for either of the above
  2. Do you only report values for the formulations (geometric mean, sd) or do you calculate and report a confidence interval?
  3. If the latter, do you use the metric in a confirmatory analysis (e.g., state an acceptance range)?
    1. Yes, always
    2. Yes, but only if clinical concerns, e.g. for long-term use analgetics, antibiotics, …
    3. Yes, but one-sided (i.e., not inferior to reference)
    4. No
      If yes, which acceptance range?
    5. 0.80-1.25
    6. 0.75-1.33
    7. 0.70-1.43
    8. other
    How do you deal with the inherent variability (low power)?
  4. Did you have any problems with your approach?
  5. Do you see a change in point of views by European regulators within the last years – especially after publication of the BE-Draft?
  6. Do you consider widening of the acceptance range in a replicate design in steady state (i.e., TTRR-RRTT), which would need measuring four profiles?
P.S.: Cmin is a quite nasty metric. In a recent study (n=40) with ≈100% PTF (Cmin ≈25% of Cmax) I saw a CVintra of 15.6% for Cmax, but 62% (!) for Cmin


Edit 1: In the final BE Guideline Cmin is not given any more as a steady state metric (for IR formulations). So the question stays valid for MR formulations – would you dare to go with scaling?

Edit 2: The comment-document (see this post) states at page 89:

By Cmin,ss we mean the concentration at the end of the dosage interval, i.e. Ctrough. However, in bioequivalence studies for immediate release formulations there is no need to report Ctrough and fluctuation. The guideline has been revised.


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