Cmin-value <LLOQ [Surveys]

posted by Helmut Homepage – Vienna, Austria, 2010-01-04 17:34 (5196 d 21:07 ago) – Posting: # 4559
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Dear beman (reads BE-man?),

❝ I define the Cmin-Value in multiple dose bioequivalence studies as the 'Last concentration within the dosing interval'.


Well, that’s option 1.c and the ‘Trough concentration’ defined by Weimann and WHO (2006).

❝ If the last value in the dosing interval is <LLOQ, which value should i use ?


Hhm, this problem applies to all definitions of Cmin. Nasty for a low accumulation index…

❝ - If i set the value to zero, the ratio T/R can't be calculated.


Sure. Though I’m not a fan of setting anything to LOQ/2, I used that approach in a recent study accepted by the German BfArM (low accumulation, concentrations ranging more than three orders of magnitute).

❝ - I can calculate a value <LLOQ (with the average half life time of the corresponding single dose study or the literature).


Well, why not use an estimate (from the half life of the particular subject in the multiple dose study)? We had a little discussion there.
Using the (average!) half life from another study is unacceptable IMHO. Even more from the literature.

❝ - I can use the Last concentration value >=LLOQ (for both the reference and the test formulation)

❝ - I can use the Last concentration value >=LLOQ (for only one formulation, for the other i use the last concentration value).


This problem is similar to the ‘missing 72 h value’ for truncated AUC. See this post for an example. Your first option would give an unbiased T/R (but is available in standard PK-software only for AUCτ; see this post). You would have to set up something on your own. The second one IMHO is ‘apples-and-oranges statistics’.

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