Bioequivalence and Bioavailability Forum

Dear Atish!

❝ 1. What are the reasons that can be given for exclusion of subject from statistical analysis, having more than two missing time points.

Where does this number two come from?

❝ 2. On what basis we can decide the uncritical region.

Depending on the drug, formulation, sampling scheme,…
Examples of critical regions are the absorption phase in the case of an IR formulation, around t_max and the (late) elimination phase.

❝ 3. By interpolation (linear in the rising part, log/linear after tmax) do you mean that we have to show un-transformed or raw data to be linear in rising part and after tmax ln-transformed data to be linear.

No, you cannot show that (because we don’t now the ‘true’ time course). Lin-up/Log-down is a crude – but useful – approximation in NCA.
If you start a poll amongst NCA experts – that’s the one probably the majority will opt for.

❝ Kindly clarify and give a breif idea about what do you mean by interpolation.

OK, have a look at one of my lectures (slides 51-53).
The profile comes from the ‘real world’; afterwards (knowing the results already) I cracked the 48 hours’ sample vial on my PC. The measured value was 3.805 ng/mL – but since I cracked the vial, suddenly I didn’t know the value any more:
If we draw a straight line (e.g. don’t attempt to deal with the situation) – that’s the linear trapezoidal rule within 36 and 72 hours. Unexpressed we treat the missing value as 4.996 ng/mL; AUC will be over-estimated. If we perform a log-linear interpolation we would get an estimated value of 3.850 ng/mL which is much closer to the ‘true’ one.
If you don’t know about this game and just treat the timepoint as missing you will end up with an overestimated AUC. Unfortunately that’s exactly the default in WinNonlin.
State the method for missing values in the protocol – and change the option in this nice piece of software.
What’s actually happening then is a calculation by the linear trapezoidal method and a switch to log/linear between 36 and 72 hours. If you don’t like this idea, you may opt for lin-up/log-down in all cases (not just the one with missing data).