Bioequivalence and Bioavailability Forum

Dear Ratnakar!

❝ We are doing this study as a multiple dose just because single dose Nasal spray dose not give detectable concentrations.

Given the advancements in bioanalytics you should have very strong arguments before claiming that it's not possible to measure the single dose profile. Even if AUC cannot be characterized after SD, EMEA's BE-draft suggests to measure C_max after SD and AUC in steady state!

❝ Now is it necessary that we have to prove Steady state in such situations also?

IMHO yes, because the superposition principle in linear PK simply is AUC_∞ (SD) = AUC_τ (SS).

❝ If yes, then we will have to follow the all steady state requirements.

I would say so.

❝ Secondly for other parameters such as %fluctuations and Cmin criteria of 80-125% CI required to be applied or not?

Difficult question. Depends on both the regulatory requirements and the point of view of the assessor(s). Generally %PTF as an aggregate metric is less variable than C_max, so it should not be problematic (for a nasty example see D. Labes' experiences). C_min is a pain in ... - especially if you have only little accumulation and values close to the LLOQ.
In many cases the variability of C_min prevents the demonstration of BE in a reasonbly powered study. You should study the literature whether this metric is important based on clinical grounds and state it in the protocol. On the other hand I have seen a lot of studies in the EU where assessors insisted on C_min within conventional BE limits...

❝ Cav should also be analysed with confidence interval or not?

No. C_av is only needed to calculate %PTF. It doesn't make sense: the PE and CI should be the same as the ones of AUC_τ.