Bioequivalence and Bioavailability Forum

Hi John & Mittyri,

❝ His conclusion was based on AUC being similar between the two sampling time schemes which I agree.

Well, these are simulated data (^…) of a fast bolus – though in the real world we never would see the highest concentration at t=0*. Note that Nathan calculated the AUC by the lin/log-trapezoidal rule (which mimics the exponentional decrease; see also another blog-post). Only with this algo there is no impact of time deviations on AUCs. If someone still uses the linear trapezoidal (why the heck?) the AUC₈ of subject 2001 (─) would be 0.55% larger than the one of subject 1001 (─).

❝ For BE studies we need to determine both AUC and Cmax equivalence between test and reference. Therefore the PK time point selection is important (if not critical).

Agree. ‘Catching’ C_max is very important in BE. The same is true if truncated/partial AUCs come into play. In steady state studies EMA requires sampling time deviations of ≤ ±5’ for the pre-dose sample and ≤ ±10’ for the sample at the end of the dosing interval.

Overall I disagree with Nathan’s conclusions, that

[…] setting sampling “windows” does not affect the PK parameters and only leads to extra work for the clinical and data management teams as they verify the time of the blood sample versus the acceptable window, record any deviations, and then supply justification for the deviations.
[…] with such an intense focus on getting a sample at a specific time, often clinical staff record incorrect blood draw times to stay “in window” rather than report the actual blood draw times.

I would still set time allowance windows and require a justification if sampling takes place outside. For Nathan’s second remark I would suggest training the clinical staff.

See also John’s weird experiences (#1, #2).

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• Injecting into the subjects’ one arm’s vein and sampling from the other at the same time? Even for a quick bolus turnaround time of the circulation is up to two minutes. Therefore, any sample taken earlier than two minutes does not make any sense. You might end up with strange low concentrations (due to the intermixing phase) which even for a one-compartment model don’t fit well into the rest of the profile.