Bioequivalence and Bioavailability Forum

Hello Hutchy,

❝ Thank you both for the swift reply... will obviously need to give this more thought!

Thinking won't solve it, you still need to find some practical ways to handle this case.

1. Replacing BLQs by zero is ok for "linear up, linear down" when you try to work out the trapezoid areas used to derive the AUCt.
   
2. This guy (gal?) will have a zero AUCt and no AUCinf.
   
3. If you do "linear up, log down" then setting a BLQ to zero on a log stretch is not viable. Here, I think EU regulators tend to accept anything like LLOQ/2 or whatever, but this is not because LLOQ/2 is pharmacokinetically qualified in any way, it is solely because it needs to have a positive value.
   
4. Replacing BLQs by zero or whatever has no particular relevance when working out kel and AUCinf.

Now think hard. Why could anyone have an apparent zero profile?

1. Zero API content in one tablet?
   
2. Did not swallow the capsule? Mouth check post dose? Puke?
   
3. Malfunctioning bioanalytical run?
   
4. Something with the matrix storage after draws?
   
5. The guy is the Usain Bolt of fast metabolisers?

You can easily get flagged for an inspection, so as much as you need to figure out if this guy's samples contribute to your understanding of the PK of the T and R, you need to convince the regulator that things are handled properly whatever you do.

Audit the whole thing, and do it well.

For example pt. a. above is not about looking at the CoA and just thinking "well, the thingy was at 101.3% of labeled content so we are all good".
Did the samples of this subject's run sit with other subject samples in the same run? Did you see anything out of the ordinary there? Did you investigate? Did the lab technician pipette the right matrix for extraction? Did the same technician pipette samples for another trial that day, if yes did the other trial also have a zero profile? Did you see irregularities when doing dissolution and F2? Was any test for potency/content/etc repeated for any reason?
Did Watson LIMS grab an output from Analyst? Did it do so correctly? Did you use a Hamilton? Did the Hamilton pressure profiles for the samples in question look normal (note: Hamiltons generate myriads of data which noone ever looks at but it is available).
If you sample the content in XYZ tablets (individually), would one of them show 0% ?
Can you do a lab investigation and look at the primary and/or secondary samples again (regardless of how the guideline is worded, this is part of an investigation, not a classical repeat)?
ISR's for that subject informative or not done yet?
And so forth.

This could all be a bit of an ordeal, but the burden associated with doing it right now is much, much smaller than the burden of an inspection later on if you get flagged, and you may get flagged if you are not very proactively pursuing explanations. So I would do these things right away.