Bioequivalence and Bioavailability Forum

Dear Daniel!

❝ I would like to know if there is a special procedure to sample collection considering AUC truncated design when the drug has a long half-life (higher than 90 hours).

No; last sample = 72 hours. I would try to concentrate on C_max.

❝ Is it correct collect samples for 2xt1/2? Considering t1/2 = 90h, sample collection until 180h. In this situation would be impossible to apply the concept of samples until 72h.

Please see this thread first.
In short the time point of truncation is triggered by the maximum gastric residence time (which by consensus is set to 72 h)   there’s no connection with t_1/2 for immediate release products.

See also WHO's guideline (Section 6.2 Study design):

‘It is currently not foreseen that there would be a need for blood samples to be collected for more than 72 hours.’

… and even more specific (Section 6.2.2 Considerations for drugs with long elimination half-lives):

‘For both cross-over and parallel-design studies, sample collection time should be adequate to ensure completion of gastrointestinal transit (approximately 2–3 days) of the pharmaceutical product and absorption of the API. Blood sampling up to 72 hours following administration should be carried out, unless shorter periods can be justified.’

The European Note for Guidance on BE (which is currently under revision – internal draft #8) will also limit the last sampling time point to 72 h.

Currently the only country I know giving some strange recommendations (i.e., no truncation for HVDs) is the FDA, stating (in Section VI.C):

‘[…] we recommend that sample collection time be adequate to ensure completion of gastro­in­tes­tinal transit (approximately 2 to 3 days) of the drug product and absorption of the drug substance. Cmax and a suitably truncated AUC can be used to characterize peak and total drug exposure, respectively. For drugs that demonstrate low intrasubject variability in distribution and clearance, an AUC truncated at 72 hours (AUC_0-72hr) can be used in place of AUC_0-t or AUC_0-inf. For drugs demonstrating high intrasubject variability in distribution and clearance, AUC truncation warrants caution. In such cases, we also recommend that sponsors and/or applicants consult the appropriate review staff.’