Bioequivalence and Bioavailability Forum

Hi sciguy!

❝ So you're saying that theoretically, BE can be concluded even after dose normalization on different dosage strengths - so long as the requirement for linear PK is fulfilled.

Yes, but it must be clear that here BE is based on a more tough assumption. Genrally (well, outside of Canada) we are not allowed to perform a dose-correction at the same strengths even if we know that actual contents differ. Imagine a CI of 77-118% and actual contents of 100% (test) and 104.91% (reference). After dose correction the formulation would pass (81.91–122.91%). We have to assume D_T=D_R despite better knowledge. Regulator’s paranoia think that you performed the study, know the outcome and afterwards falsify the CoAs.

❝ In your experience though, it sounds like reg. agencies don't like this and would rather you match up the strengths with 2x, 3x etc doses.

Yes. I keep trying; but in the light of the above I’m not very optimistic. See also there.

❝ The problem I have is that I have different strengths that are not whole number multiples of each other, for example 10 mg vs 8 mg. In this case, maybe it is acceptable to dose normalize and declare BE (assuming linear PK of course). If, however, the 10 mg vs 8 mg are different formulations, then we can't dose normalize and assess BE since we don't know what impact the formulation differences can have on f (and linear PK may no longer hold).

Yes, one example are MR methylphenidate·HCl formulations. Most MR formulations come in strengths of 5-60 mg, and Concerta in 18, 27, 36, 54, 72 mg. BE (?) studies are published with dose normalization. But: there’s a lot of data available that MPH has really linear PK.

❝ In this case, would we have to assess BE on non dose-normalized data?

Hhm, but how? If we dose-normalize your example we get e.g. 90.00-111.11%. If we don’t normalize, we get 112.50–138.89%.

That's an Ouroboros: