Using f2 for compounds that never reach 85% dissolution [Dissolution / BCS / IVIVC]

posted by wligtenberg – The Netherlands, 2017-01-03 16:48 (2641 d 07:11 ago) – Posting: # 16923
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As mentioned before, I am quite new to the bioequivalence and bioavailability field.
I was asked to look into dissolution profiles of a few compounds.

I have already implemented the F2 and mahalanobis distance in R, so the calculation is not an issue. However, I am not sure if the rules in the guidelines are sufficient to apply them in a correct manner.

For instance, we have compounds for which the RLD and the in house product never reach 85% dissolution. (lipophilic compounds in membranes/vesicles)

If I am not mistaken, the idea of having only one time point after dissolution goes above 85% is to make sure, that you don't just add arbitrary high time points to decrease the influence of the lower time points (if they would differ in the beginning).
This would allow you to always get an F2 above 50, if you just measure enough points after dissolution is at its peak.

So I guess, the reason is more that you don't want to compare time points where the dissolution has plateaued. That makes sense, in my opinion.
However, when we have compounds that already plateau before 85% we can still have this issue.

I have thought of 2 possible solutions:
1) Scale the dissolution, so that the maximum (of either product is 100%) and then calculate F2/mahalanobis as normal.
2) Define a way to detect the plateau and then use the first time point that reaches that plateau. For plateau detection we could use: have a 10% increase between each time point. Or fit a (Weibull) model and use that to define the plateau level.

I personally like the second solution better, because it doesn't change the data.
It behaves more like the normal rules, but it is also a bit more complicated.

What do you think? Or are there some rules for instances like this, that I haven't found?

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