AUC0-t / AUC0-∞ ≥80% [NCA / SHAM]

posted by Helmut Homepage – Vienna, Austria, 2009-05-22 18:29 (5509 d 08:37 ago) – Posting: # 3733
Views: 17,038

Dear Pavan!

❝ suppose the percentage ratio of AUC0-t and AUC0-inf is less than 80%.

80% of ‘covered’ AUC are literally given in only some guidelines (e.g., nothing is mentioned in FDA’s at all). Mainly they speak about ‘sufficient long sampling to get a reliable estimate of the elimination phase’, :blahblah:

A current document comes from EMEA, stating:

Provide information regarding size of extrapolated area. The extrapolated AUC should not be higher than 20% in any subject (not only the mean extrapolation).

An older one from ANVISA (2003):

The AUC0-t must be equal or greater than 80% of the ASC0-inf, except in the cases where the truncated AUC is used;

This requirement is still given in 2006’s document (in Portugese).

EMEA’s NfG (2001) states:

The sampling schedule should be planned to provide an adequate estimation of Cmax and to cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of absorption. This is generally achieved if the AUC derived from measurements is at least 80% of the AUC extrapolated to infinity. If a reliable estimate of terminal half-life is necessary, it should be obtained by collecting at least three to four samples during the terminal log linear phase.

EMEA’s BE Draft (2008) states:

For single dose studies, the percentage of AUCinf that is covered by AUCt should be reported for each subject in each period if the observation period is shorter than 72 hours. Subjects should not be excluded from the analysis on the basis of this calculation, but if the percentage is less than 80% in more than 20% of the observations then the validity of the study could be questioned.

❝ What is the justification we can give?

Stop! Think! Act! Don’t perform the BE-assessment according to the protocol! And document clearly that you haven’t done it yet. Otherwise regulators might get the impression any strategy you are developing to deal with the problem was data-driven (i.e., you played around with different methods and selected one which favours BE).

Some thoughts:

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