Bioequivalence and Bioavailability Forum

Dear dlabes !

I assume that you refer to extra vascular route of administration

1) beginning values <LLOQ:
yes I would set values below LLOQ to zero as it is a classical informative missing scenario. This gives you a clear impression of a lag-time to for the drug reaching the systemic circulation

2) intermediate values <LLOQ:
this is an interesting scenario - as far as I understand - this up and down would indicate a "re-release" of the drug during the elimination phase however, I would set these values to zero (informative missing as indicated by <LLOQ). the average concentration time profile should give you an impression of an potential re-release or simple of random variation. In the case of an unexpected behavior of the drug – the mean concentration time profile would indicate this by a distinct bump otherwise this individual values would be "averaged out".

in the case that a re-release is definitely not possible from a physiological point of view - this up and down is simple due to random variation. I would add a data handling section in the protocol clearly describing that if a concentration level post study drug administration observed after Tmax is lower than LLOQ that this concentration level and all subsequent concentration levels will be not used for calculation of any PK parameters (and set to zero for individual and average concentration time profiles).

ad boxplots) are you kidding? the sponsor would give a drug to humans based on interpretation of rather complicated confidence intervals but they are not able to read box plots. OH MY GOD !

by the way I would go for schematic-type boxplots (link, figure 18.4) indicating both, the median and the arithmetic mean.

best regards

martin