Bioequivalence and Bioavailability Forum

Hi Pash413

❝ Interestingly we observed zero concentrations throughout all the sampling points for test formulation in at-least one period in ~ 45 % subjects and zero concentrations throughout the all the sampling points for reference formulation in at-least one period in ~ 50 % subjects [Note: LLOQ was sufficiently low to capture the PK profile]. Similar results were observed for this molecule in other literature too.

We have observed this phenomenon in few of our studies including DR tablets even after staff/PI checking with a tongue spatula and keeping close eyes on volunteers that they do not vomit/cough the tablets out.

Just two point I would like to make
a) What were the time points used? In our studies we have observed that few volunteers showed one point Cmax between 24-48 hrs time points and after that the concentration fall drastically with no measurable concentrations at later points.

b) DR tablets are quite notorious and highly variable when it comes to gastric emptying. Would it be possible to check that whether tablets came out in feces as such? This might give you an idea.

c) Would it be possible for further lower the LLOQ to get better idea?

❝ 3. We have got a literature in which Cmax and AUC with zero value were assigned/imputed with a fixed value = (LLOQ/2) and data of all such subjects were included in statistical analysis. This methodology was accepted by FDA for one of the NDA. Can we adopt the same for our product for ANDA submission

This approach looks reasonable and IMHO can be used. I think Stat Gurus will let us know the pros and cons of the method soon.
But again, first you should look for the reason of getting zero concentrations and on possibility of decreasing such occurrences.