So how do you feel about that?
In BE of IR vs. IR we can be pretty sure that the slowest phase is elimination. Absorption is essentially completed after 2–4×tmax
. That’s why for EMA AUCt
is the only
metric for extent of absorption. Alternatively, you can truncate the AUC at 72 hours (contrary to the FDA independent from half-life). The 72 hours are based on GI-studies showing this cut-off as the maximum ever observed gastric transit time. Never understood why the FDA additionally
. Both metrics are highly correlated – only AUC∞
is more variable. IMHO, it is hypocritical to require both. Based on the Intersection-Union tests I cannot imagine a study passing AUC∞
and failing on AUCt
. So why all that fuzz?
MR is a different story (leaving pulsatile / multiphasic / delayed release aside). It might be possible that you cross the Rubicon of ka
(flip-flop). Remember that in BE we compare extent/rate of absorption
. IMHO, once the slowest phase represents absorption you cannot truncate the AUC anymore (regardless whether at tlast
or at 72 hours) – otherwise (if absorptions rates differ) your T/R-ratios will be biased. Therefore – as you said – we should sample long enough to reliably describe absorption. Generally estimation of λz
will not be difficult then. Even if we fail in getting an estimate, long sampling should protect us against bias. Just my two cents.
BTW, in their recent draft on BE of MR formulations EMA added AUC∞
. They are considering whether this will be the only
metric for extended (EMA’s term: prolonged) release, AUC72
is not acceptable. Maybe a (much) later truncation time point will be. Let’s see…