Bioequivalence and Bioavailability Forum

❝ In the bioequivalance study, we had deviation in time point of the blood collection, how much and how long are the deviations acceptable??

Sometimes a sample cannot be taken at the planned time after drug administration. In prin­ciple, it is always possible to use the actual time of sampling – relative to drug administration – when calculating the AUC. On the other hand, this effort frequently dose not seem to be jus­tified, since a shift of d data point in the concentration-time curve usually has only a mar­ginal effect on the area under the curve (only the partial areas surrounding the delayed sample are affected).

The sampling time points in the study protocol were selected in order to permit a description of the concentration-time profile as precisely as possible. Based on this, only those time devi­ations will be of pharmaco­kinetic relevance in which the time interval between the preceding and the affected sample or the interval between the affected and the following sample was pro­longed or shortened by, for example, more than 5%. In practice it has been proven accept­able to consider only those time deviations out of this specified range when calculating the AUC.
At later time points after drug administration the samples are commonly taken at relatively long intervals. For these samples a deviation by more than about 30 minutes should also be considered to be of possible pharmacokinetic relevance in order to allow for a conceivable circadian rhythm, even if the deviation is less than 5% of the shorter of the two surrounding time intervals. On the other hand, considering that the sampling process itself takes some time, it is not reasonable to account for any deviations of less than a minute.

This procedure for calculating pharmacokinetic parameters by ignoring any time deviations of less then 5% of the shorter of the two time intervals surrounding the sample affected has been shown by simulations to lead to estimates that differ at the most by 1.5% from the theoretical value. In unfavourable circumstances (very few samples, all deviations sys­tema­tically in one direction) the relative error may increase to 3.6%. The simulation furthermore showed that a well-chosen design (e.g. with respect to sampling times) is more important than other factors (e.g. theoretical profile, analytical accuracy).
Any sampling occuring too early is a deviation that should be reported even if pharma­co­ki­netically irrelevant, since there are only few plausible reasons why an activity should have been performed earlier than planned. When investigating the pharmacokinetics after single dosing, the predose sample, except for endogenous substances, is only used to demonstrate that there were no quantifiable concentrations preceding drug administration. This sample may therefore be taken within a reasonable time span preceding dug administration e.g. within 30 minutes; nevertheless, it will be considered during the calculations as if it has been taken simultaneously with the drug administration.