Bioequivalence and Bioavailability Forum

Hi Dan,

❝ Do you have any idea?

Not really. Steady-state, comparison of C_ss?

❝ If I use the FDA recommended study design for European submission what could be a possible reason for rejection? Is a BE study with dosing 3x1 capsule less or more sensitiv to detect possible differences in formulation than 1x1 capsule?

I don't think any general rule can apply here. If the Cmax is 20x LLOQ then all should be adequate, and this would certainly be the case here. The S:N's impact on accuracy of determinations is likely positive for all samples, but on the other hand depending on your calibration curve you may need dilutions which drag things in the other direction. Dosing at 3x recommended dose is not per se an issue for EU.

Having said all that, due to intra-batch variation of the IMPs it is always in theory better with 1 unit than 2,3,4... units (example: if the content of a tablets is normal with some mean and some variance, then the sum of three tablets is also normal with mean 3x the single mean, and the variance of the sum of three will be 3x the variance of one). This will in theory translate into an increased residual in the linear model. I am not sure I would consider this to have too much practical importance though.