Bioequivalence and Bioavailability Forum

Thanks everybody for all the responses.

Helmut

❝ [...] such a value might be physiologically impossible – especially if the value is embedded by two high concentrations.

I'm not a pharmacologist, so I don't have much knowledge regarding the impossibility of such value, but afaik there is the possibiility of an enterohepatic circulation, for example, which would make possible for the drug concentrations in plasma to have such "triangle" behaviour. Also, statisticians are mostly not in favor of outlier exclusion, and such points are outliers themselves. It's more important to understand why it happened than to just exclude it. It could have happened due to an accidental swap of samples, to enterohepatic circulation, high LLOQ or other unknown reason... We never have that smooth beautiful PK profile that we wish for, since there are drugs that has this "zig zag" PK profile. Drugs such as pentoxifylline or loratadine have by nature a behaviour that would make possible to points like that to be shown, and also we have more complicated situations like for endogenous drugs that after baseline correction might present lots of triagulations points.

❝ I don’t like the common practice of repeating only the doubtful value. We always re-analyze the two neighbouring samples.

That would be the best way, but ANVISA (as presented by Felipe in this thread) does not allow reanalysis due to PK reasons, in other to avoid a manipulation of the results.

Felipe and ElMaestro

❝ Release two reports, one using all points and another excluding those triangulation points. Go for a meeting and good luck, you'll need!

That's actually the way it is done around here now, but it's very hard to have a conclusion of the study if the rule of decision is in a "gray area"... They might go for the worst case or not.

tks

Lucas