Bioequivalence and Bioavailability Forum

Hello Kshitij!

❝ What will be the effect on the pharmacokinetic front if a particular subject was administered with only 230 ml of water in one period however, in another one, he was given 240 ml water. should this make significant difference in the bioequivalence estimation of the test formulation?

I know the solvent front in thin layer chromatography, but what's the pharmacokinetic front?

OK, that’s a 4.2% difference in fluid volume. I would not bother a second about this! The main purpose of the fluid is not to supply a solvent in the stomach – which will be ‘gone’ within a short period of time anyway – but to get the formulations without problems down the throat (prevent sticking somwhere in the esophagus). If you watched it, make a note in the subject's CRF, and continue as usual (maybe you can try to convince the subject to swallow the remaining 10 ml as well).

The main assumption in a cross-over study for BE are constant clearances throughout treatment periods (for assumptions see this post); we have no means to verify this assumption anyway. So your difference in fluid volume may simply add just a little variability to the within-subject error.

If you find a real large difference in PK responses between occasions (statistical significant outlier), according to almost all guidelines you have the possibility to exclude the subject from the evaluation (because you are able to give a clinical explanation). As always, don’t forget to make such a statement a priori in the protocol.